title: DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability.
abstract: MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been studied extensively, many of its known functions, to date, pertain to the DNA damage response (DDR) pathway. Herein we report a novel function of phosphorylated MDC1 that is independent of ATM and DNA damage and is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is anin vivotarget of Plk1 and that phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores, and midbodies. Knockdown of MDC1 or abrogation of Plk1 phosphorylation of MDC1 causes a delay of the prometaphase-metaphase transition. It is significant that mice with reduced levels of MDC1 showed an elevated level of spontaneous tumors in aged animals. Our results demonstrate that MDC1 also plays a fundamentally significant role in maintenance of genomic stability through a DDR-independent pathway.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Shao
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Carlock
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA liu8@purdue.edu.|Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000097869:Polo-Like Kinase 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C508937:MDC1 protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: MDC1; Plk1; genomic instability; mitosis; phosphorylation