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Mitosis-Specific MRN Complex Promotes a Mitotic Signaling Cascade to Regulate Spindle Dynamics and Chromosome Segregation

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Mitosis-Specific MRN Complex Promotes a Mitotic Signaling Cascade to Regulate Spindle Dynamics and Chromosome Segregation Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation Ran Xua,1, Yixi Xua,1, Wei Huoa, Zhicong Lva, Jingsong Yuanb,c, Shaokai Ninga, Qingsong Wanga, Mei Houa, Ge Gao (高歌)a, Jianguo Jia, Junjie Chend, Rong Guoa,2, and Dongyi Xua,2 aState Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; bDepartment of Radiation Oncology, Columbia University Medical Center, New York, NY 10032; cCenter for Radiological Research, Columbia University Medical Center, New York, NY 10032; and dDepartment of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030 Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved September 11, 2018 (received for review April 18, 2018) The MRE11–RAD50–NBS1 (MRN) complex is well known for partici- nases, including PLK1 (18, 19). PLK1 interacts with KIF2A spe- pating in DNA damage response pathways in all phases of cell cycle. cifically during mitosis, in a manner dependent on its kinase Here, we show that MRN constitutes a mitosis-specific complex, activity. PLK1 is also capable of directly phosphorylating KIF2A named mMRN, with a protein, MMAP. MMAP directly interacts with and enhancing its depolymerase activity (18). Here, we show that MRE11 and is required for optimal stability of the MRN complex MRN forms a mitosis-specific complex, named mMRN, with a during mitosis. MMAP colocalizes with MRN in mitotic spindles, protein, MMAP. The mMRN complex is required for PLK1 to and MMAP-deficient cells display abnormal spindle dynamics and interact with and activate its downstream substrate, KIF2A, chromosome segregation similar to MRN-deficient cells. Mechanisti- leading to spindle turnover and chromosome segregation. Our cally, both MMAP and MRE11 are hyperphosphorylated by the mi- data suggest that mMRN plays a crucial role in the PLK1–KIF2A totic kinase, PLK1; and the phosphorylation is required for assembly signaling cascade to regulate mitotic spindle dynamics. of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase, Results KIF2A, leading to spindle turnover and chromosome segregation. MMAP/C2orf44 Is One Component of the MRN Complex. We transiently Our study identifies a mitosis-specific version of the MRN complex expressedFLAG-taggedMRE11,RAD50,andNBS1inHEK293 – that acts in the PLK1 KIF2A signaling cascade to regulate spindle cells and immunoprecipitated the complexes with an anti-FLAG dynamics and chromosome distribution. antibody (Fig. 1A). Mass spectrometry identified a protein, C2orf44, in the immunoprecipitates of all of the components of the MRN C2ORF44 | MMAP | MRN | KIF2A | mMRN complex but not with the control (Fig. 1 A and B). Immunoblotting further validated this finding (Fig. 1C and SI Appendix,Fig.S1A). – – he MRE11 RAD50 NBS1 (MRN) complex plays multiple We renamed this protein as mitosis-specific MRN-associated Troles in the DNA damage response. This complex can act as a protein (MMAP). Immunoblotting (Fig. 1D) of the reciprocal sensor, a signal transducer, as well as a nuclease complex that functions in DNA double-strand break (DSB) repair by homolo- Significance gous recombination. The complex can promote activation of the ATM-dependent signaling pathway, catalyze DNA resection to – – initiate homologous recombinational repair and microhomology- The Mre11 Rad50 Nbs1 (MRN) complex is well known for par- mediated end joining, and, in some organisms, is also required ticipating in DNA damage response pathways and mediating the for the nonhomologous end-joining pathway (1, 2). Hypomorphic ATM-dependent phosphorylation signaling cascade. Hypomorphic mutations in human MRN complex have been identified in rare mutations in the human MRN complex have been identified in – autosomal recessive genetic diseases, ataxia-telangiectasia–like dis- autosomal recessive genetic diseases, ataxia-telangiectasia like order, and Nijmegen breakage syndrome (3–5). These disorders are disorder, and Nijmegen breakage syndrome. Here, we show that characterized by genome instability, hypersensitivity to ionizing ra- MRN forms a mitosis-specific complex with a protein, MMAP, diation (IR), immunodeficiency, and cancer predisposition (6, 7). which mediates a mitotic signaling cascade between PLK1 and Proper spindle assembly and subsequent spindle dynamics are KIF2A. We demonstrate that the assembly of this complex is crucial critical for accurate chromosome separation and genomic integrity for normal spindle dynamics during mitosis. Thus, our study de- scribes a signaling cascade in which PLK1-dependent phosphory- (8). Spindle assembly is mediated by two major pathways, in- – – – cluding search-and-capture of kinetochores by microtubules lation promotes the assembly of the MRN MMAP PLK1 KIF2A (MTs), and self-assembly of these MTs into a bipolar structure (9). complex, leading to mitotic spindle turnover and chromosome The latter process is dependent on the RCC1-mediated RanGTP alignment. gradient (10, 11). It was reported that the MRN complex contrib- Author contributions: R.G. and D.X. designed research; R.X., Y.X., W.H., Z.L., and S.N. utes to Ran-dependent mitotic spindle assembly by recruiting or performed research; J.Y. and J.C. contributed new reagents/analytic tools; R.X., Y.X., stabilizing RCC1 to associate with chromosomes (12). W.H., Q.W., M.H., G.G., J.J., R.G., and D.X. analyzed data; and R.X., Y.X., R.G., and D.X. Conversely, spindle dynamics is driven by active polymeriza- wrote the paper. tion and depolymerization of MTs and can generate the pulling The authors declare no conflict of interest. force for chromosome congression and segregation (9). Proper This article is a PNAS Direct Submission. spatial and temporal regulation of spindle dynamics is critical for Published under the PNAS license. normal chromosome separation and governed by multiple fac- 1R.X. and Y.X. contributed equally to this work. tors, including MT nucleators, MT depolymerase, and MT- 2To whom correspondence may be addressed. Email: [email protected] or xudongyi@ associated proteins. MT depolymerase, KIF2A, is localized to pku.edu.cn. spindle MTs and spindle poles, and plays a crucial role in spindle This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. dynamics and chromosome separation (13–17). The activity of 1073/pnas.1806665115/-/DCSupplemental. CELL BIOLOGY KIF2A is regulated through its phosphorylation by multiple ki- Published online October 8, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1806665115 PNAS | vol. 115 | no. 43 | E10079–E10088 Downloaded by guest on September 27, 2021 A Flag-IP C Flag-IP ItInput Flag IP Mock NBS1 Mock NBS1 RAD50 RAD50 MRE11 MRE11 MMAP Mock Markers MMAPs MRE11 RAD50 Markers Mock (kDa) NBS1 MMAP (kDa) 200 Flag-RAD50 200 RAD50 Flag-NBS1 116 NBS1 116 Flag-MRE11 97 MRE11 97 C2orf44 /MMAP 66 66 MMAPs Fig. 1. MMAP is one component of the MRN com- 45 45 plex. (A) Silver-stained SDS/PAGE gels showing the D IP polypeptides that were immunopurified from ex- 31 31 AP tracts of HEK293 cells expressing FLAG-tagged put M M G G Ig 21 M MRE11, RAD50, NBS1, MMAP, or MMAPs using the In 21 14 MMAP FLAG antibody. MMAPs is the short isoform of MMAP. 14 MRE11 As a control, a mock IP (Mock) was performed using untransfected HEK293 cells. (B) The proteins that were B RAD50 identified in the indicated immunoprecipitates using Flag-IP Idenfied NBS1 mass spectrometry. The numbers of peptides are aver- proteins Mock MRE11 RAD50 NBS1 MMAP MMAPs aged over two experiments. (C) Immunoblot showing MRE11 0 69. 5 52 34 5 0 the immunoprecipitation of FLAG-tagged MRE11, RAD50 0 163 168.5 23.5 15 2 Flag IP NBS1 0 18 56.5 76.5 2 0 RAD50, and NBS1. (D) Immunoblot showing the MMAP MMAP 0 5.5 4.5 1 77 57 F immunoprecipitation. For each immunoprecipitation, 8 KIF2A 0 0 0 0 43 0 extract of 1 × 10 HEK293 cells was used. (E) Schematic Mock MMAP MMAPs PLK1000090 MRE11 representation of the human MMAP isoforms. The MMAP (NP_079479.1) and MMAPs (NP_001135791.1) NBS1 isoforms were identified by searching the National RAD50 Center for Biotechnology Information NR database. CC, E 1 432 552 583 616 676 721 MMAP WD40 CC SH3 KIF2A coiled-coil motif; SH3, SH3 domain; WD40, WD40 repeat Pi PLK1 domain. A phosphorylated cluster was marked by a 1 622 MMAPs WD40 CC Flag-MMAP brown box. (F) Immunoblot showing the immunopre- Flag-MMAPs cipitation of FLAG-tagged MMAP and MMAPs. −/− immunoprecipitation with antiendogenous MMAP antibodies function of MMAP in DSB repair, we generated MMAP revealed that the MRN complex is present in the MMAP- HCT116 cells (SI Appendix,Fig.S4A and B) and found that these associated complexes, demonstrating that MMAP is a compo- cells displayed normal sensitivity to IR or camptothecin (CPT) (SI nent of the MRN complex. In contrast, CtIP, which interacts Appendix,Fig.S4C), both of which can induce DSBs. These results with MRN complex to initiate DNA resection, is not present in suggest that, unlike the MRN complex, MMAP and its associated the MMAP-associated complexes (SI Appendix, Fig. S1B), im- MMAP–MRN complex are dispensable for DSB repair. plicating that the MMAP-associated MRN complex may not be required for homologous recombinational repair. MMAP–MRN Is a Mitosis-Specific Complex. In addition to the MRN MMAP is expressed only in vertebrates (SI Appendix,Fig.S2). complex, KIF2A and PLK1 were found to coimmunoprecipitate There are two MMAP isoforms in the human genome database with FLAG–MMAP by both mass spectrometry and immuno- (Fig. 1E). The long isoform (MMAP) contains an N-terminal blotting analyses (Fig. 1 B and F). The interactions between WD40 repeat domain, a central coiled-coil motif, and a C-terminal MMAP and these two proteins are likely mediated by the C- SH3 domain; the short isoform (MMAPs) lacks the SH3 domain- terminal region of MMAP because only the long isoform of containing C terminus.
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