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Dynamic chromatin tethering of MDC1 regulates genome stability.

Joshua R Heyza·Mariia Mikhova·Cody Phillips·Shomaila Mehmood·Gloria I Perez·David G Broadbent·Jens C Schmidt
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Abstract

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions because they disrupt the connectivity of the DNA strand. Homologous recombination (HR) is a high-fidelity DSB repair pathway that copies the sequence spanning the break from a homologous template, but how DNA ends are held together during HR remains unclear. Here we demonstrate that the proline-serine-threonine (PST) repeat region of Mediator of DNA Damage Checkpoint 1 (MDC1) is a multivalent nucleosome-binding domain, sufficient to tether chromatin in multiple contexts. In interphase, the constitutive chromatin association of MDC1 is critical for RAD51 loading and efficient HR. In mitosis, PST-mediated chromatin binding is attenuated by phosphorylation, preventing aberrant chromosomal interactions while preserving DNA tethering by the MDC1-TOPBP1-CIP2A complex. In total, this work demonstrates that the PST repeat region of MDC1 is a multivalent nucleosome-binding domain with tunable affinity that supports DSB repair by HR and maintains genome stability during mitosis.

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Genomic InstabilityChromatinDNA Breaks, Double-StrandedCell Cycle ProteinsHumansNucleosomesMitosisAdaptor Proteins, Signal TransducingTrans-ActivatorsNuclear ProteinsAnimalsRad51 RecombinasePhosphorylationIntracellular Signaling Peptides and ProteinsDNA-Binding ProteinsHomologous RecombinationProtein BindingRecombinational DNA RepairDNA RepairJournal Article

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Joshua R Heyza, Mariia Mikhova, Cody Phillips, Shomaila Mehmood, Gloria I Perez, David G Broadbent, Jens C Schmidt. 2026-09-07. Dynamic chromatin tethering of MDC1 regulates genome stability.. https://doi.org/10.1093/nar%2Fgkag866

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