MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis.
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Date
2019-05-02ICR Author
Author
Leimbacher, P-A
Jones, SE
Shorrocks, A-MK
de Marco Zompit, M
Day, M
Blaauwendraad, J
Bundschuh, D
Bonham, S
Fischer, R
Fink, D
Kessler, BM
Oliver, AW
Pearl, LH
Blackford, AN
Stucki, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Humans
DNA Damage
Chromosomal Instability
Genomic Instability
Carrier Proteins
DNA-Binding Proteins
Trans-Activators
Nuclear Proteins
Histones
Signal Transduction
Mitosis
G1 Phase
DNA Repair
Phosphorylation
Genome, Human
DNA Breaks, Double-Stranded
Language
eng
Date accepted
2019-02-11
License start date
2019-05
Citation
Molecular cell, 2019, 74 (3), pp. 571 - 583.e8
Publisher
CELL PRESS