Homologous Recombination and the Formation of Complex Genomic Rearrangements

Abstract

The maintenance of genome integrity involves multiple independent DNA damage avoidance and repair mechanisms. Yet, the origin and pathways of the focal chromosomal reshuffling phenomena collectively referred to as chromothripsis remain mechanistically obscure. Here, we discuss the role, mechanisms, and regulation of HR in the formation of simple and complex chromosomal rearrangements. We emphasize features of the recently characterized Multi-invasions Induced Rearrangement (MIR) pathway, which uniquely amplifies the initial DNA damage. HR intermediates and cellular contexts at risk for genomic stability are discussed along with the emerging roles of various classes of nucleases in the formation of genome rearrangements. Longread sequencing and improved mapping of repeats should enable better appreciation of the significance of recombination in generating genomic rearrangements.

DNA barcoding reveals that injected transgenes are predominantly processed by homologous recombination in mouse zygote

“…5). On the contrary, remaining embryos had few (#4, 6,9) or zero (#1, 5, 10) abnormal transgene junctions. The list of some sequenced deletions and rearrangements is available in Supplementary material next to the corresponding concatemer maps.…”

“…Homology-based pathways involve invasion of singlestranded DNA filaments originating from DSB ends into homologous template region, resulting in formation of a D-loop and DNA synthesis. Different HR outcomes are possible, depending on the D-loop processing (6). In synthesis-dependent strand annealing (SDSA), restored DNA end is released after D-loop disruption, and anneals with the second DSB end.…”

“…Double-strand break repair (DSBR) operates when the displaced strand from template anneals to the second broken DNA end. This way, both invading ends become physically linked in a double Holliday junction (dHJ) that could be resolved with or without crossing-over (6). With the development of CRISPR-based genome editing, the focus has shifted to other roles of DNA repair pathways: HR is exploited for precise genetic modifications, such as transgene knock-ins, and NHEJ is used to knock-out genes (7,8).…”

The many types of heterogeneity in replicative senescence

“…When repair fails, adaptation to the checkpoint allows for the propagation of molecular structures-such as resected telomeres, terminally deleted telomeres, repair intermediates, stalled and collapsed replication forks, or fused telomeres-that would otherwise maintain an active checkpoint and would not be inherited by the progeny. The resolution of these structures over several cell divisions may subsequently lead to widespread complex chromosomal rearrangements (Beyer & Weinert, 2016;Coutelier et al, 2018;Hackett, Feldser, & Greider, 2001;Hackett & Greider, 2003;Piazza & Heyer, 2019). Adaptation could also contribute to genome instability by forcing defective and asymmetric mitosis, leading to aneuploid cells (Bender et al, 2018;Galgoczy & Toczyski, 2001;Kaye et al, 2004).…”

Centromere scission drives chromosome shuffling and reproductive isolation

“…As a result, chromosome rearrangements during mitosis can cause mutations, gene disruption, copy number variations, as well as alter the expression of genes near the breakpoints 4 . Cancer cells show a high level of chromosome rearrangements as compared to healthy cells, and this contributes to critical pathological conditions observed in these cells, such as activation of oncogenes 5, 6 .…”