Homologous Recombination Nonhomologous End Joining Interstrand Cross-Link Repair Nucleotide Excision Repair Mismatch Repair

Total Page：16

File Type：pdf, Size：1020Kb

Homologous Recombination Nonhomologous End Joining Interstrand Cross-Link Repair Nucleotide Excision Repair Mismatch Repair

DNA repair pathways Homologous recombination Nonhomologous end joining Interstrand cross-link repair Nucleotide excision repair UV DNA crosslinkers Ionizing radiation Ionizing radiation Genotoxic chemicals Genotoxic chemicals Free radicals Free radicals Mechanical stress Mechanical stress Global genome Transcription FAAP24 ICL repair coupled repair MHF1 Lesion recognition and FANCM replicative fork convergence XPC HR23B MHF2 Transcription P XPE block PARP1 P P ATM ATM Mre11 Mre11 CSA H2A H2AX ATM Rad50 γ-H2AX γ- P P ATM Rad50 P P XPC HR23B RNA Pol I/II γ-H2AX Nbs1 Nbs1 SMC1 P H4K20me2 P P CSB Mre11 FANCM, FAAP24, MHF1, MHF2 (lesion recognition) P P Rad50 Mre11 P P Poly ubiquitin Nbs1 ATM P P FANCT, FANCL (D2-I ubiquitination) P 53BP1 Histones Rad50 Histones XPG ERCC1 histones Strand tethering FANCA, B, C, E, F, G TFIID Rap80 ATM Nbs1 Mdc1 P FAAP20, 100 XPD TFB5 P P Replicative helicase eviction XPB XPF Abraxas P P and fork approach at -1 position P P Rnf8 P BRCC36 RPA XPA Caesin Kinase2 Ku / Lig4 dependent Ku / Lig4 independent Ubc13 Homologous pathway pathway γH2A.X recombination XPC HR23B BRCA1 P MRN ATM complex Rag 1/2 Resection 5’ CtIP CMG 3’ V D J 3’ CtIP Facnoni 5’ Anemia Replicative helicase ERCC1 MRN Core UHRF1 ATM Resection Cdc45 XPF complex Complex XPG P MCM2-7 TFIID GINS XPA XPD XPB TFB5 V D J CMG BRCA2 RPA P Rad51BCD Hairpin DNA Bard1 BRCA1 XRCC2/3 ends Rad51 monomers ATR ub Rad52 Rad54 FANC1 P RFC Polδ/ε Rad51BCD P FANCD2 ub XRCC2/3 DNA PKcs and BRCA1 P Ku70 Rad52 Nucleolytic incisionand BRCA2 Ku70 RPA 5’ Ku80 unhooking by NER 3’ Ku80 DNA Ligase 3’ DNA PKcs 5’ Artemis Homology search BRCA2 P PCNA and D-loop formation Rad52 BRCA1 Hairpin DNA cut ub P by Artemis Rad51BCD FANC1 XRCC2/3 P xpf FANCD2 ub Mismatch repair MUS81 FAN1 Rad54 Ku70 PARP1 SLX4 MutSα 5’ Ku70 PARP1 (Msh2 Msh6) Ku80 MutLα 5’ Ku80 3’ (Mlh1 Pms2) P Microhomology 3’ mediated strand Leading DNA PKcs Recognition MutL annealing strand α and incision Ku70 mismatch Strand invasion Ku70 Ku80 Lagging Ku80 strand mismatch DNA PKcs Translesion synthesis P DNA synthesis Strand opening and processing MutSα by exonuclease 5’ Fen1 PNKP activity of WRN DNA 5’ REV1 Pol or Polζ WRN WRN (REV3-REV7) DNA Pol Flap excision Exo1 Removal Exo1 Polβ Homologous chromosome DNA ligation Ligation and formation of Holliday Junction DNA RPA DNA XRCC1 Ligase 3 XRCC4 Ligase 4 Non-crossover DNA PCNA Ligase1 (cut both junctions XLF vertically or horizontally) Polδ Holliday Homologous Recombination Polδ Resynthesis junction resolvase No deletion Short deletion PCNA Accurate repair Inaccurate repair Crossover (cut both grey or both blue arrows) RPA Find out more at www.abcam.com/dnadamage Created by Abcam in collaboration with James Haber and Farokh Dotiwala, (Brandeis University), and Michela Clerici (University of Milan, Bicocca). Copyright © 2017Abcam. All rights reseverved. .

Copy Link

Recommended publications

Regulation of DNA Cross-Link Repair by the Fanconi Anemia/BRCA Pathway
Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway Hyungjin Kim and Alan D. D’Andrea1 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA The maintenance of genome stability is critical for sur- and quadradials, a phenotype widely used as a diagnostic vival, and its failure is often associated with tumorigen- test for FA. esis. The Fanconi anemia (FA) pathway is essential for At least 15 FA gene products constitute a common the repair of DNA interstrand cross-links (ICLs), and a DNA repair pathway, the FA pathway, which resolves germline defect in the pathway results in FA, a cancer ICLs encountered during replication (Fig. 1A). Specifi- predisposition syndrome driven by genome instability. cally, eight FA proteins (FANCA/B/C/E/F/G/L/M) form Central to this pathway is the monoubiquitination of a multisubunit ubiquitin E3 ligase complex, the FA core FANCD2, which coordinates multiple DNA repair activ- complex, which activates the monoubiquitination of ities required for the resolution of ICLs. Recent studies FANCD2 and FANCI after genotoxic stress or in S phase have demonstrated how the FA pathway coordinates three (Wang 2007). The FANCM subunit initiates the pathway critical DNA repair processes, including nucleolytic in- (Fig. 1B). It forms a heterodimeric complex with FAAP24 cision, translesion DNA synthesis (TLS), and homologous (FA-associated protein 24 kDa), and the complex resem- recombination (HR). Here, we review recent advances in bles an XPF–ERCC1 structure-specific endonuclease pair our understanding of the downstream ICL repair steps (Ciccia et al.
[Show full text]
Open Full Page
CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data deﬁning the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders.
[Show full text]
Gene Section Review
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review XRCC2 (X-ray repair cross complementing 2) Paul R Andreassen, Helmut Hanenberg Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA; [email protected] (PRA); Department of Pediatrics III, University Children's Hospital Essen, University Duisburg- Essen, Essen Germany; [email protected] (HH) Published in Atlas Database: November 2017 Online updated version : http://AtlasGeneticsOncology.org/Genes/XRCC2ID334ch7q36.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69759/11-2017-XRCC2ID334ch7q36.pdf DOI: 10.4267/2042/69759 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2019 Atlas of Genetics and Cytogenetics in Oncology and Haematology Clinically, the only known FA-U patient in the Abstract world exhibits severe congenital abnormalities, but XRCC2 is one of five somatic RAD51 paralogs, all had not developed, by seven years of age, the bone of which have Walker A and B ATPase motifs. marrow failure and cancer that are often seen in Each of the paralogs, including XRCC2, has a patients from other FA complementation groups. function in DNA double-strand break repair by Keywords homologous recombination (HR). However, their Fanconi anemia, Breast Cancer Susceptibility, individual roles are not as well understood as that Tumor Suppressor, Homologous Recombination, of RAD51 itself. DNA Repair, RAD51 Paralog The XRCC2 protein forms a complex (BCDX2) with three other RAD51 paralogs, RAD51B, RAD51C and RAD51D. It is believed that the Identity BCDX2 complex mediates HR downstream of Other names: FANCU BRCA2 but upstream of RAD51, as XRCC2 is HGNC (Hugo): XRCC2 involved in the assembly of RAD51 into DNA damage foci.
[Show full text]
Understanding the Role of Rad52 in Homologous Recombination for Therapeutic Advancement
Author Manuscript Published OnlineFirst on October 15, 2012; DOI: 10.1158/1078-0432.CCR-11-3150 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The Role of Rad52 in Homologous Recombination MOLECULAR PATHWAYS: Understanding the role of Rad52 in homologous recombination for therapeutic advancement Benjamin H. Lok 1,2 and Simon N. Powell 1 1 Memorial Sloan-Kettering Cancer Center, New York, NY 2 New York University School of Medicine, New York, NY Corresponding author: Simon N. Powell, MD PhD Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Mailing address: 1250 1st Avenue, Box 33, New York, NY 10065 Telephone: 212-639-6072 Facsimile: 212-794-3188 E-mail: [email protected] Conflicts of interest. The authors have no potential conflict of interest to report. 1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 15, 2012; DOI: 10.1158/1078-0432.CCR-11-3150 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The Role of Rad52 in Homologous Recombination Table of Contents Abstract ......................................................................................................................................................... 2 Background ..................................................................................................................................................
[Show full text]
Use of the XRCC2 Promoter for in Vivo Cancer Diagnosis and Therapy
Chen et al. Cell Death and Disease (2018) 9:420 DOI 10.1038/s41419-018-0453-9 Cell Death & Disease ARTICLE Open Access Use of the XRCC2 promoter for in vivo cancer diagnosis and therapy Yu Chen1,ZhenLi1,ZhuXu1, Huanyin Tang1,WenxuanGuo1, Xiaoxiang Sun1,WenjunZhang1, Jian Zhang2, Xiaoping Wan1, Ying Jiang1 and Zhiyong Mao 1 Abstract The homologous recombination (HR) pathway is a promising target for cancer therapy as it is frequently upregulated in tumors. One such strategy is to target tumors with cancer-specific, hyperactive promoters of HR genes including RAD51 and RAD51C. However, the promoter size and the delivery method have limited its potential clinical applications. Here we identified the ~2.1 kb promoter of XRCC2, similar to ~6.5 kb RAD51 promoter, as also hyperactivated in cancer cells. We found that XRCC2 expression is upregulated in nearly all types of cancers, to a degree comparable to RAD51 while much higher than RAD51C. Further study demonstrated that XRCC2 promoter is hyperactivated in cancer cell lines, and diphtheria toxin A (DTA) gene driven by XRCC2 promoter specifically eliminates cancer cells. Moreover, lentiviral vectors containing XRCC2 promoter driving firefly luciferase or DTA were created and applied to subcutaneous HeLa xenograft mice. We demonstrated that the pXRCC2-luciferase lentivirus is an effective tool for in vivo cancer visualization. Most importantly, pXRCC2-DTA lentivirus significantly inhibited the growth of HeLa xenografts in comparison to the control group. In summary, our results strongly indicate that virus-mediated delivery of constructs built upon the XRCC2 promoter holds great potential for tumor diagnosis and therapy.
[Show full text]
Biochemistry of Recombinational DNA Repair
BiochemistryBiochemistry ofof RecombinationalRecombinational DNADNA Repair:Repair: CommonCommon ThemesThemes StephenStephen KowalczykowskiKowalczykowski UniversityUniversity ofof California,California, DavisDavis •Overview of genetic recombination and its function. •Biochemical mechanism of recombination in Eukaryotes. •Universal features: steps common to all organisms. HomologousHomologous RecombinationRecombination AB ab+ Ab aB+ Genesis:Genesis: ScienceScience andand thethe BeginningBeginning ofof TimeTime How does recombination occur? And why? DNADNA ReplicationReplication CanCan ProduceProduce dsDNAdsDNA BreaksBreaks andand ssDNAssDNA GapsGaps RepairRepair ofof DNADNA BreaksBreaks Non-Homologous Homologous End-Joining (NHEJ) Recombination (HR) (error-prone) (error-free) dsDNA Break-Repair Synthesis-Dependent ssDNA Annealing (DSBR) Strand-Annealing (SSA) (SDSA) DoubleDouble--StrandStrand DNADNA BreakBreak RepairRepair 5' 3' 3' 5' + 3' 5' 5' 3' Initiation 1 5' 3' Helicase and/or 3' 5' nuclease 2 5' 3' 3' 3' 3' 5' Homologous Pairing & DNA Strand 3 Exchange 3' 5' 5' 3' RecA-like protein 5' 3' Accessory proteins 3' 3' 5' 4 3' 5' 5' 3' 5' 3' 3' 5' DNA Heteroduplex 5 Branch migration Extension proteins 3' 5' 5' 3' 5' 3' 3' 5' Resolution 6 Resolvase Spliced Patched ProteinsProteins InvolvedInvolved inin RecombinationalRecombinational DNADNA RepairRepair E. coli Archaea S. cerevisiae Human Initiation RecBCD -- -- -- SbcCD Mre11/Rad50 Mre11/Rad50/Xrs2 Mre11/Rad50/Nbs1 RecQ Sgs1(?) Sgs1(?) RecQ1/4/5 LM/WRN(?) RecJ -- ExoI ExoI UvrD -- Srs2 -- Homologous Pairing RecA RadA Rad51 Rad51 & DNA Strand SSB SSB/RPA RPA RPA Exchange RecF(R) RadB/B2/B3(?) Rad55/57 Rad51B/C/D/Xrcc2/3 RecO -- Rad52 Rad52 -- -- Rad59 -- -- Rad54 Rad54/Rdh54 Rad54/54B Brca2 DNA Heteroduplex RuvAB Rad54 Rad54 Rad54 Extension RecG -- -- RecQ Sgs1(?) RecQL/4/5 LM/WRN(?) Resolution RuvC Hjc/Hje -- -- -- -- Mus81/Mms4 Mus81/Mms4 ProteinsProteins InvolvedInvolved inin RecombinationalRecombinational DNADNA RepairRepair 5' 3' E.
[Show full text]
Distinct Pathways of Homologous Recombination Controlled by the SWS1–SWSAP1–SPIDR Complex ✉ Rohit Prakash 1 , Thomas Sandoval1, Florian Morati 2, Jennifer A
ARTICLE https://doi.org/10.1038/s41467-021-24205-6 OPEN Distinct pathways of homologous recombination controlled by the SWS1–SWSAP1–SPIDR complex ✉ Rohit Prakash 1 , Thomas Sandoval1, Florian Morati 2, Jennifer A. Zagelbaum3, Pei-Xin Lim 1, Travis White1, Brett Taylor 1, Raymond Wang1, Emilie C. B. Desclos4, Meghan R. Sullivan5, Hayley L. Rein5, Kara A. Bernstein 5, Przemek M. Krawczyk4, Jean Gautier3, Mauro Modesti 2, Fabio Vanoli 1 & ✉ Maria Jasin 1 1234567890():,; Homology-directed repair (HDR), a critical DNA repair pathway in mammalian cells, is complex, leading to multiple outcomes with different impacts on genomic integrity. However, the factors that control these different outcomes are often not well understood. Here we show that SWS1–SWSAP1-SPIDR controls distinct types of HDR. Despite their requirement for stable assembly of RAD51 recombinase at DNA damage sites, these proteins are not essential for intra-chromosomal HDR, providing insight into why patients and mice with mutations are viable. However, SWS1–SWSAP1-SPIDR is critical for inter-homolog HDR, the first mitotic factor identified specifically for this function. Furthermore, SWS1–SWSAP1-SPIDR drives the high level of sister-chromatid exchange, promotes long-range loss of hetero- zygosity often involved with cancer initiation, and impels the poor growth of BLM helicase- deficient cells. The relevance of these genetic interactions is evident as SWSAP1 loss prolongs Blm-mutant embryo survival, suggesting a possible druggable target for the treat- ment of Bloom syndrome. 1 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2 Cancer Research Center of Marseille, CNRS, Inserm, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
[Show full text]
An Overview of DNA Repair Mechanisms in Plants Compared to Mammals
Cell. Mol. Life Sci. (2017) 74:1693–1709 DOI 10.1007/s00018-016-2436-2 Cellular and Molecular Life Sciences REVIEW Protecting DNA from errors and damage: an overview of DNA repair mechanisms in plants compared to mammals Claudia P. Spampinato1 Received: 8 August 2016 / Revised: 1 December 2016 / Accepted: 5 December 2016 / Published online: 20 December 2016 Ó Springer International Publishing 2016 Abstract The genome integrity of all organisms is con- methods and reporter systems for gene expression and stantly threatened by replication errors and DNA damage function studies. Here, I provide a current understanding of arising from endogenous and exogenous sources. Such base DNA repair genes in plants, with a special focus on A. pair anomalies must be accurately repaired to prevent thaliana. It is expected that this review will be a valuable mutagenesis and/or lethality. Thus, it is not surprising that resource for future functional studies in the DNA repair cells have evolved multiple and partially overlapping DNA ﬁeld, both in plants and animals. repair pathways to correct speciﬁc types of DNA errors and lesions. Great progress in unraveling these repair mecha- Keywords DNA repair Á Photolyases Á BER Á NER Á nisms at the molecular level has been made by several MMR Á HR Á NHEJ talented researchers, among them Tomas Lindahl, Aziz Sancar, and Paul Modrich, all three Nobel laureates in Chemistry for 2015. Much of this knowledge comes from Introduction studies performed in bacteria, yeast, and mammals and has impacted research in plant systems. Two plant features All organisms are constantly exposed to environmental should be mentioned.
[Show full text]
Genetic Polymorphism of DNA Repair Genes (XRCC1, XRCC2 & XRCC3)
International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571 Original Research Article Genetic Polymorphism of DNA Repair Genes (XRCC1, XRCC2 & XRCC3) in Breast Cancer Patients from Rural Maharashtra Kailas D. Datkhile1, Suresh J. Bhosale2, Madhavi N. Patil1, Tejasvi S. Khamkar1, Pratik P. Durgawale1, Satish V. Kakade3 1Molecular & Genetic Laboratory, 2Department of Surgery, 3Department of Preventive and Social Medicine, Krishna Institute of Medical Sciences University, Taluka-Karad, Dist-Satara, Pin-415 110 Maharashtra, India Corresponding Author: Kailas D. Datkhile Received: 17/01/2017 Revised: 28/01/2017 Accepted: 30/01/2017 ABSTRACT Background & Objectives: Breast cancer is a major concern of health risk, moreover the leading cause of cancer causing deaths in women of rural parts of India. In this study, we focused to determine the frequency of polymorphisms in DNA repair genes, XRCC1 at codon (cd) 194, cd 280, cd 399, XRCC 2 at cd 188 and XRCC3 at cd 241 to evaluate their role in breast cancer risk. Methods: We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze XRCC genes polymorphisms in 150 breast cancer women and 200 age matched disease-free controls. Results: The result from our study showed that allele frequencies of selected genes were not statistically different between the groups for XRCC1 Trp194, Gln399, XRCC2 His188 and XRCC3 Met241. XRCC1 His280 (OR= 4.14; 95% CI= (2.63-6.53); p= <0.0001) genotype significantly increased the risk of breast cancer. Interpretation & conclusions: This study indicates that polymorphisms in cd280 of XRCC1 gene could play a role in modifying genetic susceptibility of individuals towards breast cancer among women from rural Maharashtra.
[Show full text]
Bloom Syndrome Complex Promotes FANCM Recruitment to Stalled Replication Forks and Facilitates Both Repair and Traverse of DNA Interstrand Crosslinks
OPEN Citation: Cell Discovery (2016) 2, 16047; doi:10.1038/celldisc.2016.47 ARTICLE www.nature.com/celldisc Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks Chen Ling1, Jing Huang2,4, Zhijiang Yan1, Yongjiang Li1, Mioko Ohzeki3, Masamichi Ishiai3, Dongyi Xu1,5, Minoru Takata3, Michael Seidman2, Weidong Wang1 1Lab of Genetics, National Institute on Aging, National Institute of Health, Baltimore, MD, USA; 2Lab of Molecular Gerontology, National Institute on Aging, National Institute of Health, Baltimore, MD, USA; 3Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan The recruitment of FANCM, a conserved DNA translocase and key component of several DNA repair protein complexes, to replication forks stalled by DNA interstrand crosslinks (ICLs) is a step upstream of the Fanconi anemia (FA) repair and replication traverse pathways of ICLs. However, detection of the FANCM recruitment has been technically challenging so that its mechanism remains exclusive. Here, we successfully observed recruitment of FANCM at stalled forks using a newly developed protocol. We report that the FANCM recruitment depends upon its intrinsic DNA trans- locase activity, and its DNA-binding partner FAAP24. Moreover, it is dependent on the replication checkpoint kinase, ATR; but is independent of the FA core and FANCD2–FANCI complexes, two essential components of the FA pathway, indicating that the FANCM recruitment occurs downstream of ATR but upstream of the FA pathway. Interestingly, the recruitment of FANCM requires its direct interaction with Bloom syndrome complex composed of BLM helicase, Topoisomerase 3α, RMI1 and RMI2; as well as the helicase activity of BLM.
[Show full text]
FANCG Promotes Formation of a Newly Identified Protein Complex
Oncogene (2008) 27, 3641–3652 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ORIGINAL ARTICLE FANCG promotes formation of a newly identiﬁed protein complex containing BRCA2, FANCD2 and XRCC3 JB Wilson1, K Yamamoto2,9, AS Marriott1, S Hussain3, P Sung4, ME Hoatlin5, CG Mathew6, M Takata2,10, LH Thompson7, GM Kupfer8 and NJ Jones1 1Molecular Oncology and Stem Cell Research Group, School of Biological Sciences, University of Liverpool, Liverpool, UK; 2Department of Immunology and Medical Genetics, Kawasaki Medical School, Kurashiki, Okayama, Japan; 3Department of Biochemistry, University of Cambridge, Cambridge, UK; 4Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA; 5Division of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR, USA; 6Department of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK; 7Biosciences and Biotechnology Division, L441, Lawrence Livermore National Laboratory, Livermore, CA, USA and 8Department of Pediatrics, Division of Hematology-Oncology, Yale University School of Medicine, New Haven, CT, USA Fanconi anemia (FA) is a human disorder characterized intricate interface between FANC and HRR proteins in by cancer susceptibility and cellular sensitivity to DNA maintaining chromosome stability. crosslinks and other damages. Thirteen complementation Oncogene (2008) 27, 3641–3652; doi:10.1038/sj.onc.1211034; groups and genes are identiﬁed, including BRCA2, which published online 21 January 2008 is defective in the FA-D1 group. Eight of the FA proteins, including FANCG, participate in a nuclear core complex Keywords: Fanconi anemia; ATR; interstrand cross- that is required for the monoubiquitylation of FANCD2 links; DNA repair; RAD51 paralog; replication restart; and FANCI.
[Show full text]
A Structure-Specific Nucleic Acid-Binding Domain Conserved Among DNA Repair Proteins
A structure-specific nucleic acid-binding domain conserved among DNA repair proteins Aaron C. Masona, Robert P. Rambob, Briana Greera, Michael Pritchetta, John A. Tainerb, David Cortezc, and Brandt F. Eichmana,c,1 aDepartment of Biological Sciences, Vanderbilt University, Nashville, TN 37232; bLife Sciences Division, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; and cDepartment of Biochemistry, Vanderbilt School of Medicine, Nashville, TN 37232 Edited by James M. Berger, Johns Hopkins University School of Medicine, Baltimore, MD, and approved April 17, 2014 (received for review December 30, 2013) SMARCAL1, a DNA remodeling protein fundamental to genome 1), also known as HARP (HepA-related protein), is one of several integrity during replication, is the only gene associated with the ATP-dependent motor proteins capable of fork regression and im- developmental disorder Schimke immuno-osseous dysplasia (SIOD). portant for genetic stability, including Rad54, RecQ paralogs, BLM, SMARCAL1-deficient cells show collapsed replication forks, S-phase WRN, FANCM, ZRANB3, HLTF/Rad5, T4 bacteriophage UvsW, cell cycle arrest, increased chromosomal breaks, hypersensitivity to archaeal HelQ/Hel308/Hjm, and Escherichia coli RecG (18–26). genotoxic agents, and chromosomal instability. The SMARCAL1 cat- SMARCAL1 is a distant SNF2 family member of dsDNA trans- alytic domain (SMARCAL1CD) is composed of an SNF2-type double- locating chromatin remodeling proteins (27) with a binding prefer- ence for branched DNA structures, and has been shown to catalyze stranded DNA motor ATPase fused to a HARP domain of unknown A function. The mechanisms by which SMARCAL1 and other DNA ATP-dependent regression of model replication forks (Fig. 1 ), branch migration of Holliday junctions, and reannealing of RPA- translocases repair replication forks are poorly understood, in part – because of a lack of structural information on the domains outside coated plasmids (28 30).
[Show full text]