MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis

被引：89

作者：

Leimbacher, Pia-Amata ^{[1
,2
]}

Jones, Samuel E. ^{[3
,4
]}

Shorrocks, Ann-Marie K. ^{[3
,4
]}

Zompit, Mara de Marco ^{[1
,2
]}

Day, Matthew ^{[5
]}

Blaauwendraad, Jordy ^{[1
,2
]}

Bundschuh, Diana ^{[1
,2
]}

Bonham, Sarah ^{[6
]}

Fischer, Roman ^{[6
]}

Fink, Daniel ^{[1
,2
]}

Kessler, Benedikt M. ^{[6
]}

Oliver, Antony W. ^{[5
]}

Pearl, Laurence H. ^{[5
]}

Blackford, Andrew N. ^{[3
,4
]}

Stucki, Manuel ^{[1
,2
]}

机构：

[1] Univ Hosp, Dept Gynecol, Wagistr 14, CH-8952 Schlieren, Switzerland

[2] Univ Zurich, Wagistr 14, CH-8952 Schlieren, Switzerland

[3] Univ Oxford, John Radcliffe Hosp, Med Res Council, Dept Oncol,Weatherall Inst Mol Med, Oxford OX3 9DS, England

[4] Univ Oxford, Med Res Council, Oxford Inst Radiat Oncol, Canc Res UK, Oxford OX3 7DQ, England

[5] Univ Sussex, Sch Life Sci, Genome Damage & Stabil Ctr, Canc Res UK DNA Repair Enzymes Grp, Falmer BN1 9RQ, England

[6] Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Oxford OX3 7FZ, England

来源：

MOLECULAR CELL | 2019年 / 74卷 / 03期

基金：

瑞士国家科学基金会;

关键词：

DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; MRN COMPLEX; CHECKPOINT; REPAIR; NBS1; 53BP1; OLIGOMERIZATION; TRANSMISSION; RECOGNITION;

D O I：

10.1016/j.molcel.2019.02.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In mitosis, cells inactivate DNA double-strand break (DSB) repair pathways to preserve genome stability. However, some early signaling events still occur, such as recruitment of the scaffold protein MDC1 to phosphorylated histone H2AX at DSBs. Yet, it remains unclear whether these events are important for maintaining genome stability during mitosis. Here, we identify a highly conserved protein-interaction surface in MDC1 that is phosphorylated by CK2 and recognized by the DNA-damage response mediator protein TOPBP1. Disruption of MDC1-TOPBP1 binding causes a specific loss of TOPBP1 recruitment to DSBs in mitotic but not interphase cells, accompanied by mitotic radiosensitivity, increased micronuclei, and chromosomal instability. Mechanistically, we find that TOPBP1 forms filamentous structures capable of bridging MDC1 foci in mitosis, indicating that MDC1-TOPBP1 complexes tether DSBs until repair is reactivated in the following G1 phase. Thus, we reveal an important, hitherto-unnoticed cooperation between MDC1 and TOPBP1 in maintaining genome stability during cell division.

引用

页码：571 / +

页数：21

共 61 条

[1] Oligomerization of TopBP1 is necessary for the localization of TopBP1 to mitotic centrosomes [J].