Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

MAD1L1 (mitotic arrest deficient 1 like 1) Keli Lima, João Agostinho Machado-Neto Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, [email protected] (KL), Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo [email protected] (JAMN), São Paulo, Brazil.

Published in Atlas Database: February 2018 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAD1L1ID41226ch7p22.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68948/02-2018-MAD1L1ID41226ch7p22.pdf DOI: 10.4267/2042/68948

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2018 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Location 7p22.3 MAD1L1 is coiled-coil that binds to improperly attached kinetochrore, what results in DNA/RNA recruitment and interaction with MAD2L1, activation of the mitotic checkpoint complex, Description inhibition of the anaphase-promoting The entire MAD1L1 is approximately 417.1 Kb complex/cyclosome and arrest. During (start: 1815792 and end: 2232971 bp; orientation: interphase, MAD1L1 regulates entrance at Minus strand). The MAD1L1 gene encodes for 6 nuclear pore complexes (MAD2L1-dependent transcript variants. The transcript variant 1 (start: mechanism) and Golgi apparatus-related functions 1815792 and end: 2232948 bp; orientation: Minus (MAD2L1-independent mechanism). Alterations in strand; 19 exons; mRNA: 2754 bp) is the longest MAD1L1 are associated with chromosomal transcript variant. Transcript variant 2 (mRNA: 2717 instability, aneuploidy, and cancer susceptibility. bp), transcript variant 3 (mRNA: 2714 bp) and The present review contains data on MAD1L1 DNA, transcript variant 4 (mRNA: 2538 bp) differs in the RNA, protein encoded and function. 5' UTR compared to transcript variant 1. The Keywords transcript variants 1-4 encode the protein isoform a MAD1L1; Mitotic arrest deficient 1 like 1; ; (718 aa protein). The transcript variant 5 (mRNA: Spindle checkpoint; Cell cycle; 2376 bp; 17 exons) lacks some exons in the 5' UTR segregation and displays an alternate exon in the 5' coding region, what results in an alternative start codon, Identity frameshift, and a shorter and distinct protein (isoform b; 626 aa). The transcript variant 6 is the Other names shortest transcript variant (start: 1815792 and end: MAD1, PIG9, TP53I9, TXBP181, MAD1 Mitotic 1940550 bp; 4 exons; mRNA: 1318 bp), it displays Arrest Deficient Like 1, Mitotic Checkpoint MAD1 an alternative 5'-terminal exon, uses an in-frame start Protein Homolog, Tax-Binding Protein 181, MAD1- codon and encodes the protein isoform c (174 aa). Like Protein 1, Tumor Protein P53 Inducible Protein 9, HsMAD1, HMAD1 HGNC (Hugo) MAD1L1

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(10) 429 MAD1L1 (mitotic arrest deficient 1 like 1)

Protein

Figure 1. MAD1L1 protein structure. MAD1L1 protein contains a MAD1L1 oligomerization domain, MAD2L1-binding domain and RLK motif (Arg-Leu-Lys; essential for BUB1 and BUB3 interactions). This figure was adapted from Canman et al., 2002; Sironi et al., 2002.

Description Expression MAD1L1 is a 718-residue coiled-coil protein that Ubiquitous. interacts with MAD2L1, and is composite of a MAD1L1 oligomerization domain, MAD2L1- Localisation binding domain and RLK motif (Arg-Leu-Lys; During mitosis, MAD1L1 is localized essential for BUB1 and BUB3 interactions) predominantly at unattached . During (Canman et al., 2002; Sironi et al., 2002) (Figure 1). interphase, MAD1L1 is localized in perinuclear MAD1L1-MAD2L1 complexes form a tetramer-like region, nuclear pore complex, centrosome and Golgi structure due to the parallel intermolecular coiled- apparatus (Campbell et al., 2001; Rodriguez-Bravo coil between α 1 helices from different MAD1L1 et al., 2014; Wan et al., 2014). molecules (Nasmyth, 2005; Sironi et al., 2002).

Figure 2. MAD1L1 functions in spindle assembly checkpoint. (Upper panel) During mitosis, MAD1L1 binds to improperly attached kinetochrore, what results in recruitment and interaction with MAD2L1, and activation of the mitotic checkpoint complex (MCC). The MCC inhibits the anaphase-promoting complex/cyclosome (APC/C) and leads to cell cycle arrest. (Lower panel) In absence of unattached , MAD1L1/MAD2L1 complex is not recruited, what results in chromosome segregation during anaphase. This figure was created using Servier Medical Art tools (http://www.servier.com).

Function perform its functions (Campbell et al., 2001; Wright et al., 2017). The complex MAD1L1/MAD2L1 MAD1L1 belongs to the assembly control of the binds to improperly attached kinetochrore, induces mitotic spindle, which acts as a component capable MAD1L1 phosphorylation by MPS1, and acts as an of blocking the onset of the anaphase if the anchor for the formation of other protein are not correctly aligned on the interactions, including MAD2L1-CDC20 complex. metaphase plate (Hardwick and Murray, 1995). The The molecular events upon MAD1L1 and MAD1L1 protein has approximately 83 kDa and unattached kinetochores interaction lead to the interacts with other , such as MAD2L1, to

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(10) 430

MAD1L1 (mitotic arrest deficient 1 like 1) formation of mitotic checkpoint complex (MCC), Somatic inhibition of anaphase-promoting Recurrent mutations in the MAD1L1 gene are rare, complex/cyclosome (APC/C), and cell cycle arrest and 153 missense substitution, 69 synonymous (Reviewed by Schuyler et al., 2012 and London and substitution, 8 nonsense substitution, 1 frameshift Biggins, 2014) (Figure 2). insertion and 8 frameshift deletion mutations are Rodriguez-Bravo and colleagues (Rodriguez-Bravo reported in COSMIC (Catalogue of Somatic et al., 2014) reported that the MAD1L1-MAD2L1 Mutations in Cancer; complex anchored to the nuclear pore complexes http://cancer.sanger.ac.uk/cancergenome/projects/c emits an inhibitory signal that limits the speed of the osmic). Similar findings were reported in cBioPortal mitosis, facilitating corrections of possible errors, (http://www.cbioportal.org), which includes 41824 which would avoid a cell cycle arrest. Alterations in cancer samples: somatic mutation frequency in MAD1L1 are associated with chromosomal MAD1L1 was 0.5% (195 mutations, being 166 instability and aneuploidy (Avram et al., 2014; missense and 29 truncating mutations). Analyzing Tsukasaki et al., 2001). together, mutation, amplification, deep deletion and Wan and colleagues (Wan et al., 2014) reported an multiple alterations, the total of cancer samples with elegant mechanistic study that described the non- any type of alteration was 570 (1.4%). related spindle assembly checkpoint and MAD2L1 independent functions for MADlL1. During interphase, MAD1L1 is localized in the Golgi Implicated in apparatus, and participates in integrin secretion, Colorectal cancer adhesion, mobility, cell migration and PTK2 (FAK) In HCT116 colorectal carcinoma cell line, MAD1L1 signaling pathway (Wan et al., 2014). silencing disturbed the spindle checkpoint and Homology leaded to aneuploidy (Kienitz et al., 2005). On the MAD1L1 has a high homology among different other hand, the induction of MAD1L1 species (Table 1). overexpression resulted in aberrant mitotic timing, Table 1. Comparative identity of human MAD1L1 aneuploidy and resistance to apoptosis in DLD1 with other species cells, a chromosomally stable colorectal cancer cell line (Ryan et al., 2012). The presence of the % Identity for: genotype His/His for the MAD1L1 Arg558His Homo sapiens Symbol Protein DNA (rs1801368) polymorphism was associated with MAD1L1 increased risk for colorectal cancer, using a dominant model, in a Chinese cohort (Zhong et al., vs. P. troglodytes MAD1L1 99.4 99.4 2015). Liver cancer vs. M. mulatta MAD1L1 98.4 96.7 MAD1L1 expression was observed in 70% of new early diagnosed cases and 30% of recurrence vs. C. lupus MAD1L1 84.0 84.3 hepatocellular carcinoma patients, suggesting that MAD1L1 84.7 85.4 the loss of MAD1L1 may be involved in disease vs. B. taurus progression (Nam et al., 2008). MAD1L1 was found Mad1l1 81.4 81.4 to be methylated in 50% of hepatocellular carcinoma vs. M. musculus cell lines and primary samples tested. Low MAD1L1 methylation was associated with increased tumor Mad1l1 83.4 82.3 vs. R. norvegicus size and recurrence in hepatocellular carcinoma patients (Cui et al., 2016). Sze and colleagues (Sze vs. G. gallus MAD1L1 70.0 73.2 et al., 2008) identified a novel splicing variant of MAD1L1, which was found overexpressed in 24% vs. X. tropicalis 63.0 65.0 of hepatocellular carcinoma samples. Using functional studies, the authors showed that the vs. D. rerio mad1l1 54.1 60.6 ectopic expression of this novel splicing variant results mitotic checkpoint impairment and vs. D. melanogaster Mad1 28.9 45.0 aneuploidy hematoma cell lines (Sze et al., 2008). Lung cancer AgaP_AGAP006632 28.8 47.7 vs. A. gambiae An initial screening for MAD1L1 mutations in 49 lung cancer patients found one sample with somatic (Source: http://www.ncbi.nlm.nih.gov/homologene) mutation (T299A) and 1 sample with a possible

germline mutation (R556H). Coe and colleagues (Coe et al., 2006) reported that the gain of a region Mutations on 7p22.3, including 350 Kbp fragment centered at

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(10) 431

MAD1L1 (mitotic arrest deficient 1 like 1)

MAD1L1, was observed in 13 out of 14 small-cell MAD1L1 and MIR125B, a miRNA associated with lung cancers (H187, H378, H889, H1607, H1672, the suppression of malignant phenotype, in primary H2107, H2141, H2171, HCC33, H82, H289, H524, samples from head and neck/oral cancer patients. H526, and H841) and in none of normal (BL289, Recently, the t(5;7)(q34;p22) with fusion gene BL1607, BL1672, BL2107, BL2141, and BL2171) RARS /MAD1L1 was identified in 10% of cell lines analyzed. Using immunohistochemistry nasopharyngeal carcinoma and head and neck cancer analysis, MAD1L1 positive expression was found to samples (Zhong et al., 2017). Functional studies be higher in lymph node metastasis and primary indicated that RARS/MAD1L1 enhances cell tumor samples from small-cell lung cancer patients proliferation, clonogenicity and tumorigenicity compared to adjacent non-cancerous tissue samples (Zhong et al., 2017). (Li et al., 2016). In small-cell lung cancer, the Kidney cancer presence of MAD1L1 expression was associated with advanced stage of the disease, increased tumor Using quantitative PCR, Pinto and colleagues (Pinto size, higher incidence of lymph node metastasis and et al., 2007) reported that MAD1L1 is expressed at recurrence, and it was an independent predictor of low levels in chromophobe renal cell carcinoma poor survival outcomes (Li et al., 2016). In a cohort compared to normal kidney samples. The authors containing 1000 lung cancer patients and 1000 also reported that MAD1L1 mRNA levels are healthy donors, the genotype His/His for the reduced in samples from clear cell kidney carcinoma MAD1L1 Arg558His (rs1801368) polymorphism compared to healthy donors (Pinto et al., 2008). was associated with lung cancer risk (Guo et al., Ovarian cancer 2010). MAD1L1 mRNA levels were found to be Breast cancer downregulated in chemoresistant compared to MAD1L1 was frequently higher expressed in tumor chemosensitive epithelial ovarian tumors (Ju et al., compared to non-malignant or normal breast cancer 2009). Santibáñez and colleagues (Santibanez et al., samples (Ryan et al., 2012; Yuan et al., 2006) and 2013) reported that the genotype AA for the increased levels of MAD1L1 were associated with polymorphism MAD1L1 G1673A (rs1801368) was poor survival outcomes (Ryan et al., 2012). associated with advanced epithelial ovarian cancer Conversely, high cytoplasm expression of MAD1L1 risk and that the allele A was significantly associated was observed in both, normal and breast cancer with increased aneuploid cells in ovarian tumor samples. However, nuclear MAD1L1 expression samples. Functional studies indicate that the AA was significantly more frequent in breast cancer genotype is also associated with higher frequency of (28%) than normal (2%) samples (Sun et al., 2013). micronuclei and nondisjunction events (Santibanez In the same study, the author also reported that et al., 2013). nuclear MAD1L1 was associated with lower age Glioma onset, increased tumor size, higher tumor stage, MAD1L1 was increased in grade IV presence of TP53 mutations and disease subtypes, gliomas compared to normal brain tissues (Bie et al., and positive nuclear MAD1L1 was an independent 2011). predictor of worse clinical outcomes in breast cancer patients (Sun et al., 2013). In MCF-7, a breast cancer Leukemia cell line, siRNA-mediate MAD1L1 silencing MAD1L1 is highly expressed in leukemia cell lines increased migration and reduced E-cadherin (Jurkat and K562) compared to normal peripheral expression (Chen et al., 2012). blood mononuclear cells. In normal leukocytes, cell Gastric cancer proliferation induction by PHA plus IL2 increased MAD1L1 expression (Iwanaga and Jeang, 2002). Using proteomic approaches in primary samples of gastric carcinomas and its corresponding non- Lymphoma cancerous gastric mucosa, MAD1L1 was identified Using proteomics and transcriptomics approaches, as lower expressed in gastric carcinoma samples MAD1L1 was higher expressed in follicular (Nishigaki et al., 2005). Later, the same research lymphoma - compared to mantle cell lymphoma - group reported that MAD1L1 was downregulated in derived cell lines (Weinkauf et al., 2007) . 47% of gastric adenomas and 60% of gastric carcinomas, and advanced carcinomas presented Myeloproliferative neoplasm lower levels compared to early carcinomas (Osaki et Using whole-genome sequencing, Sloma and al., 2007). In MKN-1, a gastric carcinoma cell line, colleagues (Sloma et al., 2017) reported the presence ectopic MAD1L1 expression reduced proliferation of R270W heterozygous mutation in MAD1L1 gene and cell cycle progression (Osaki et al., 2007). in unusual case of BCR / ABL1 - and JAK2 V617F - positive chronic myeloid leukemia during chronic Head and neck/oral cancer phase and accelerate phase. However, upon blast Bhattacharjya and colleagues (Bhattacharjya et al., crisis evolution, the MAD1L1R270W mutation was 2013) described a negative correlation between found in homozygosis. The authors also reported the

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(10) 432

MAD1L1 (mitotic arrest deficient 1 like 1)

MAD1L1R270W mutation in an additional case of spindle checkpoint gene expression. PLoS One. JAK2V617F -positive essential thrombocythemia (1 2011;6(10):e25631 out of 101 myeloproliferative neoplasm cases tested) Campbell MS, Chan GK, Yen TJ. Mitotic checkpoint (Sloma et al., 2017). proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase. J Cell Sci. 2001 Mar;114(Pt Prostate cancer 5):953-63 MAD1L1 heterozygous mutations were found in 2 Canman JC, Sharma N, Straight A, Shannon KB, Fang G, out of 7 prostate cancer cell lines (LNCaP: Salmon ED. Anaphase onset does not require the R556C R359Q microtubule-dependent depletion of kinetochore and MAD1L1 , and LPC4: MAD1L1 ) and 2 out centromere-binding proteins. J Cell Sci. 2002 Oct 1;115(Pt R59C of 33 (MAD1L1 and a stop codon at 318) 19):3787-95 primary samples from prostate carcinoma patients Chatterjee S, Castiglione E. (Tsukasaki et al., 2001). UDPgalactose:glucosylceramide beta 1----4- Testicular germ cell tumor galactosyltransferase activity in human proximal tubular cells from normal and familial hypercholesterolemic Using a large cohort of testicular germ cell tumor and homozygotes. Biochim Biophys Acta. 1987 Jan healthy donors, and genome-wide association study 20;923(1):136-42 as approach, Chung and colleagues (Chung et al., Chen Y, Yeh PC, Huang JC, Yeh CC, Juang YL. The 2013) identified that the SNP rs12699477 of spindle checkpoint protein MAD1 regulates the expression MAD1L1 was associated with testicular germ cell of E-cadherin and prevents cell migration. Oncol Rep. 2012 Feb;27(2):487-91 tumor risk. Chung CC, Kanetsky PA, Wang Z, Hildebrandt MA, Koster R, Skotheim RI, Kratz CP, Turnbull C, Cortessis VK, Bakken To be noted AC, Bishop DT, Cook MB, Erickson RL, Fosså SD, Jacobs KB, Korde LA, Kraggerud SM, Lothe RA, Loud JT, Rahman Initially, the MAD1L1 (mitotic arrest deficient 1 like N, Skinner EC, Thomas DC, Wu X, Yeager M, Schumacher 1) gene located in chromosome 7p22.3 was known FR, Greene MH, Schwartz SM, McGlynn KA, Chanock SJ, as MAD1. However, the MXD1 (MAX dimerization Nathanson KL. Meta-analysis identifies four new loci protein 1) gene located in chromosome 2p13.3 was associated with testicular germ cell tumor. Nat Genet. 2013 also known as MAD1, what generated confusion in Jun;45(6):680-5 the literature. Therefore, it is recommended that the Coe BP, Lee EH, Chi B, Girard L, Minna JD, Gazdar AF, HUGO nomenclature should be used in current Lam S, MacAulay C, Lam WL. Gain of a region on 7p22.3, containing MAD1L1, is the most frequent event in small-cell studies involving both to avoid lung cancer cell lines. Genes Chromosomes Cancer. 2006 misinterpretation. Jan;45(1):11-9

+/- Cui C, Lu Z, Yang L, Gao Y, Liu W, Gu L, Yang C, Wilson Data from the crossing between MAD1L1 mice J, Zhang Z, Xing B, Deng D, Sun ZS. Genome-wide suggest that total deletion of the gene resulted in identification of differential methylation between primary embryonic lethality (Iwanaga et al., 2007). MAD1L1 and recurrent hepatocellular carcinomas. Mol Carcinog. haploinsufficient mice had a higher incidence of 2016 Jul;55(7):1163-74 cancer, including hepatocellular carcinoma, Guo Y, Zhang X, Yang M, Miao X, Shi Y, Yao J, Tan W, Sun rhabdomyosarcoma, osteosarcoma, T, Zhao D, Yu D, Liu J, Lin D. Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 hemangiosarcoma, uterine sarcoma and lung cancer. genes and their impact on susceptibility to lung cancer. J In addition, treatment with antineoplastic drug, Med Genet. 2010 Sep;47(9):616-22 vincristine, significantly increased tumor +/- Hardwick KG, Murray AW. Mad1p, a phosphoprotein development in MAD1L1 mice, but not in component of the spindle assembly checkpoint in budding MAD1L1+/+ mice, indicating that MAD1L1 plays a yeast. J Cell Biol. 1995 Nov;131(3):709-20 relevant role in genomic stability and carcinogenesis Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, (Iwanaga et al., 2007; Rao et al., 2009). Peloponese JM Jr, Li Y, Ward JM, Benezra R, Jeang KT. Heterozygous deletion of mitotic arrest-deficient protein 1 Recently, a genetic variation of MAD1L1 gene (MAD1) increases the incidence of tumors in mice. Cancer (rs1801368) has been identified as a potential Res. 2007 Jan 1;67(1):160-6 candidate for contributing to mosaic loss of Iwanaga Y, Jeang KT. Expression of mitotic spindle chromosome Y and cancer susceptibility in large checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 cohorts (Wright et al., 2017). mutant. Cancer Res. 2002 May 1;62(9):2618-24 Ju W, Yoo BC, Kim IJ, Kim JW, Kim SC, Lee HP. References Identification of genes with differential expression in Avram S, Mernea M, Mihailescu DF, Seiman CD, Seiman chemoresistant epithelial ovarian cancer using high-density DD, Putz MV. Mitotic checkpoint proteins Mad1 and - oligonucleotide microarrays. Oncol Res. 2009;18(2-3):47- structural and functional relationship with implication in 56 genetic diseases. Curr Comput Aided Drug Des. Kienitz A, Vogel C, Morales I, Müller R, Bastians H. Partial 2014;10(2):168-81 downregulation of MAD1 causes spindle checkpoint Bie L, Zhao G, Cheng P, Rondeau G, Porwollik S, Ju Y, Xia inactivation and aneuploidy, but does not confer resistance XQ, McClelland M. The accuracy of survival time prediction towards taxol. Oncogene. 2005 Jun 16;24(26):4301-10 for patients with glioma is improved by measuring mitotic

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(10) 433

MAD1L1 (mitotic arrest deficient 1 like 1)

Li D, Meng Q, Zhang H, Feng T, Liu M, Cai L. Mitotic arrest Sloma I, Mitjavila-Garcia MT, Feraud O, Griscelli F, Oudrhiri deficient-like 1 is correlated with poor prognosis in small-cell N, El Marsafy S, Gobbo E, Divers D, Proust A, Smadja DM, lung cancer after surgical resection. Tumour Biol. 2016 Desterke C, Carles A, Ma Y, Hirst M, Marra MA, Eaves CJ, Apr;37(4):4393-8 Bennaceur-Griscelli A, Turhan AG. Whole-genome analysis reveals unexpected dynamics of mutant subclone London N, Biggins S. Signalling dynamics in the spindle development in a patient with JAK2-V617F-positive chronic checkpoint response. Nat Rev Mol Cell Biol. 2014 myeloid leukemia. Exp Hematol. 2017 Sep;53:48-58 Nov;15(11):736-47 Sun Q, Zhang X, Liu T, Liu X, Geng J, He X, Liu Y, Pang D. Nam CW, Park NH, Park BR, Shin JW, Jung SW, Na YW, Increased expression of mitotic arrest deficient-like 1 Seo JH. Mitotic checkpoint gene MAD1 in hepatocellular (MAD1L1) is associated with poor prognosis and insensitive carcinoma is associated with tumor recurrence after surgical to Taxol treatment in breast cancer. Breast Cancer Res resection. J Surg Oncol. 2008 Jun 1;97(7):567-71 Treat. 2013 Jul;140(2):323-30 Nasmyth K. How do so few control so many? Cell. 2005 Mar Sze KM, Ching YP, Jin DY, Ng IO. Role of a novel splice 25;120(6):739-46 variant of mitotic arrest deficient 1 (MAD1), MAD1beta, in Nishigaki R, Osaki M, Hiratsuka M, Toda T, Murakami K, mitotic checkpoint control in liver cancer. Cancer Res. 2008 Jeang KT, Ito H, Inoue T, Oshimura M. Proteomic Nov 15;68(22):9194-201 identification of differentially-expressed genes in human Tsukasaki K, Miller CW, Greenspun E, Eshaghian S, gastric carcinomas. Proteomics. 2005 Aug;5(12):3205-13 Kawabata H, Fujimoto T, Tomonaga M, Sawyers C, Said Osaki M, Inoue T, Yamaguchi S, Inaba A, Tokuyasu N, JW, Koeffler HP. Mutations in the mitotic check point gene, Jeang KT, Oshimura M, Ito H. MAD1 (mitotic arrest MAD1L1, in human cancers. Oncogene. 2001 May deficiency 1) is a candidate for a tumor suppressor gene in 31;20(25):3301-5 human stomach. Virchows Arch. 2007 Oct;451(4):771-9 Wan J, Zhu F, Zasadil LM, Yu J, Wang L, Johnson A, Pinto M, Soares MJ, Cerveira N, Henrique R, Ribeiro FR, Berthier E, Beebe DJ, Audhya A, Weaver BA. A Golgi- Oliveira J, Jerónimo C, Teixeira MR. Expression changes of localized pool of the mitotic checkpoint component Mad1 the MAD mitotic checkpoint gene family in renal cell controls integrin secretion and cell migration. Curr Biol. carcinomas characterized by numerical chromosome 2014 Nov 17;24(22):2687-92 changes. Virchows Arch. 2007 Apr;450(4):379-85 Weinkauf M, Christopeit M, Hiddemann W, Dreyling M. Pinto M, Vieira J, Ribeiro FR, Soares MJ, Henrique R, Proteome- and microarray-based expression analysis of Oliveira J, Jerónimo C, Teixeira MR. Overexpression of the lymphoma cell lines identifies a p53-centered cluster of mitotic checkpoint genes BUB1 and BUBR1 is associated differentially expressed proteins in mantle cell and follicular with genomic complexity in clear cell kidney carcinomas. lymphoma. Electrophoresis. 2007 Dec;28(23):4416-26 Cell Oncol. 2008;30(5):389-95 Wright DJ, Day FR, Kerrison ND, Zink F, Cardona A, Sulem Rao CV, Yamada HY, Yao Y, Dai W. Enhanced genomic P, Thompson DJ, Sigurjonsdottir S, Gudbjartsson DF, instabilities caused by deregulated microtubule dynamics Helgason A, Chapman JR, Jackson SP, Langenberg C, and chromosome segregation: a perspective from genetic Wareham NJ, Scott RA, Thorsteindottir U, Ong KK, studies in mice. Carcinogenesis. 2009 Sep;30(9):1469-74 Stefansson K, Perry JRB. Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and Rodriguez-Bravo V, Maciejowski J, Corona J, Buch HK, overlap with cancer susceptibility. Nat Genet. 2017 Collin P, Kanemaki MT, Shah JV, Jallepalli PV. Nuclear May;49(5):674-679 pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor. Cell. 2014 Feb Yuan B, Xu Y, Woo JH, Wang Y, Bae YK, Yoon DS, Wersto 27;156(5):1017-31 RP, Tully E, Wilsbach K, Gabrielson E. Increased expression of mitotic checkpoint genes in breast cancer Ryan SD, Britigan EM, Zasadil LM, Witte K, Audhya A, cells with chromosomal instability. Clin Cancer Res. 2006 Roopra A, Weaver BA. Up-regulation of the mitotic Jan 15;12(2):405-10 checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons. Proc Natl Zhong Q, Liu ZH, Lin ZR, Hu ZD, Yuan L, Liu YM, Zhou AJ, Acad Sci U S A. 2012 Aug 14;109(33):E2205-14 Xu LH, Hu LJ, Wang ZF, Guan XY, Hao JJ, Lui VWY, Guo L, Mai HQ, Chen MY, Han F, Xia YF, Grandis JR, Zhang X, Santibáñez M, Gallardo D, Morales F, López A, Prada D, Zeng MS. The RARS-MAD1L1 Fusion Gene Induces Mendoza J, Castro C, de León DC, Oñate LF, Perez D, Cancer Stem Cell-like Properties and Therapeutic Mohar A, Herrera LA. The MAD1 1673 G → A Resistance in Nasopharyngeal Carcinoma. Clin Cancer polymorphism alters the function of the mitotic spindle Res. 2018 Feb 1;24(3):659-673 assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to Zhong R, Chen X, Chen X, Zhu B, Lou J, Li J, Shen N, Yang treatment in patients with advanced epithelial ovarian Y, Gong Y, Zhu Y, Yuan J, Xia X, Miao X. MAD1L1 cancer. Pharmacogenet Genomics. 2013 Apr;23(4):190-9 Arg558His and MAD2L1 Leu84Met interaction with smoking increase the risk of colorectal cancer. Sci Rep. 2015 Jul Schuyler SC, Wu YF, Kuan VJ. The Mad1-Mad2 balancing 17;5:12202 act--a damaged spindle checkpoint in chromosome instability and cancer. J Cell Sci. 2012 Sep 15;125(Pt This article should be referenced as such: 18):4197-206 Lima K, Machado-Neto JA. MAD1L1 (mitotic Sironi L, Mapelli M, Knapp S, De Antoni A, Jeang KT, arrest deficient 1 like 1). Atlas Genet Cytogenet Musacchio A. Crystal structure of the tetrameric Mad1- Oncol Haematol. 2018; 22(10):429-434. Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint. EMBO J. 2002 May 15;21(10):2496-506

Atlas Genet Cytogenet Oncol Haematol. 2018; 22(10) 434