Mitotic tethering enables en masse inheritance of a shattered micronuclear chromosome

Abstract

Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s)1, is an ubiquitous2 mutational process generating localized complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by missegregation errors in mitosis3,4 or DNA metabolism5-7 that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or upon mitotic entry6,8-10. Here, we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of Mediator of DNA damage checkpoint 1 (MDC1), DNA Topoisomerase II Binding Protein 1 (TOPBP1), and Cellular Inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome missegregation and shattering after transient inactivation of the spindle assembly checkpoint. Pan-cancer analysis of transcriptome and whole-genome sequencing data revealed that chromothriptic genome rearrangements were accompanied by elevated expression of MDC1, TOPBP1, and CIP2A. Thus, chromatin-bound tethers maintain proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers.

Microhomology‐mediated repair machinery and its relationship with HPV‐mediated oncogenesis

“…One feature that contributes to hotspots of HPV DNA integration are common and cell‐type specific chromosomal fragile sites, which can develop DBS during replication stress which also can lead to alteration in gene expression levels 20,82–84 . Recent studies have also found that HPV integration can occur at DBS associated with chromothripsis, which as previously mentioned can generate genome‐wide chromosomal changes and have MHS at repair junctions 85–88 . Integration next to coding regions or even distant flanking regions of genes can lead to changes like amplification, rearrangement, translocation, or long‐range cis interactions.…”

The two sides of chromosomal instability: drivers and brakes in cancer

“…78,115,[122][123][124][125][126][127][128][129][130][131][132][133] Chromothripsis has been associated with various tumor types and can lead to both numerical and structural CIN, altering gene expression patterns and driving changes in cellular behavior. 122,[287][288][289] Chromothripsis can contribute to tumorigenesis in multiple ways, either beneficial or deleterious. For instance, while DNA damage can be a cause of CIN as discussed in DSBs from replication stress, it is also a significant consequence of CIN, as chromothripsis could induce extensive DNA damage and destabilize tumor cell growth, leading to apoptosis.…”

A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels

“…TopBP1 is an active protein during mitosis and is critical for maintaining genome integrity (16,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). The ability of E2-K111Q to remove TopBP1 from mitotic chromatin indicated this protein may disrupt mitosis.…”