MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Cells inactivate DNA double-strand break (DSB) repair during mitosis to maintain genome stability.
• Early signaling events, like MDC1 recruitment to DSBs, occur but their role in mitosis is unclear.

Purpose of the Study:

• Investigate the role of MDC1-TOPBP1 interactions in maintaining genome stability during mitosis.
• Clarify the function of early DSB signaling events in mitotic genome integrity.

Main Methods:

• Protein interaction analysis to identify conserved binding surfaces in MDC1.
• Phosphorylation assays using CK2.
• Assessment of TOPBP1 recruitment to DSBs in mitotic and interphase cells.
• Phenotypic analysis including radiosensitivity, micronuclei formation, and chromosomal instability.

Main Results:

• A conserved protein-interaction surface on MDC1, phosphorylated by CK2, binds TOPBP1.
• Disruption of MDC1-TOPBP1 binding specifically impairs TOPBP1 recruitment to mitotic DSBs.
• MDC1-TOPBP1 complexes tether DSBs during mitosis, with TOPBP1 forming filamentous structures.
• Loss of this interaction leads to mitotic radiosensitivity, micronuclei, and chromosomal instability.

Conclusions:

• MDC1 and TOPBP1 cooperate to maintain genome stability during mitosis by tethering DSBs.
• This interaction is crucial for preventing genomic instability during cell division.
• Reveals a previously unrecognized mechanism for DSB management in mitosis.