Repair of DNA Breaks by Break-Induced Replication

Abstract

Double-strand DNA breaks (DSBs) are the most lethal type of DNA damage, making DSB repair critical for cell survival. However, some DSB repair pathways are mutagenic and promote genome rearrangements, leading to genome destabilization. One such pathway is break-induced replication (BIR), which repairs primarily one-ended DSBs, similar to those formed by collapsed replication forks or telomere erosion. BIR is initiated by the invasion of a broken DNA end into a homologous template, synthesizes new DNA within the context of a migrating bubble, and is associated with conservative inheritance of new genetic material. This mode of synthesis is responsible for a high level of genetic instability associated with BIR. Eukaryotic BIR was initially investigated in yeast, but now it is also actively studied in mammalian systems. Additionally, a significant breakthrough has been made regarding the role of microhomology-mediated BIR in the formation of complex genomic rearrangements that underly various human pathologies. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The immediate early protein 1 of human herpesvirus 6B counteracts ATM activation in an NBS1-dependent manner

“…Thereby, integration models where SSA or RAD51-independent BIR trigger integration following extensive accumulation of single-strand DNA generated at stalled replication fork are still plausible. One attractive model is that the integration of HHV-6B occurs during mitotic DNA synthesis (MiDAS), a RAD52-dependent BIR mechanism that is initiated upon replication fork stall that remain unresolved at the start of mitosis, a problem often observed at DNA locus that are hard to replicate such as telomeres (9,23,76). Such mechanism is NBS1-and RAD51-independent and is mediated by RAD52, POLD3 as well as the structure-specific nuclease MUS81-EME1.…”

“…RAD51 or RAD52 recombinases promote DNA repair by HDR and SSA (22). Both recombinases also promote DNA repair of oneend DSB, but their exact contribution to that latter pathway is still unclear (23).…”

Srs2 and Pif1 as Model Systems for Understanding Sf1a and Sf1b Helicase Structure and Function

“…Cells can use BIR for the repair of one-ended DSBs that arise at eroded telomeres or when a replication fork encounters a single-strand nick ( Figure 5 E) [ 135 , 136 ]. Although BIR can be used to repair one-ended DSBs, it is also highly mutagenic (~1000-fold higher than normal replication), and can lead to a loss of heterozygosity, chromosomal translocations, and copy number variations, all of which are hallmarks of cancer [ 136 ]. During BIR, Rad51 and Rad54 catalyze strand invasion to pair the broken DSB end with a homologous dsDNA template [ 136 ].…”

“…Although BIR can be used to repair one-ended DSBs, it is also highly mutagenic (~1000-fold higher than normal replication), and can lead to a loss of heterozygosity, chromosomal translocations, and copy number variations, all of which are hallmarks of cancer [ 136 ]. During BIR, Rad51 and Rad54 catalyze strand invasion to pair the broken DSB end with a homologous dsDNA template [ 136 ]. Notably, Pif1, which is not required for normal S-phase DNA replication, is essential for BIR [ 130 , 131 , 136 , 137 ].…”

“…During BIR, Rad51 and Rad54 catalyze strand invasion to pair the broken DSB end with a homologous dsDNA template [ 136 ]. Notably, Pif1, which is not required for normal S-phase DNA replication, is essential for BIR [ 130 , 131 , 136 , 137 ]. Polymerase delta (polδ) drives DNA synthesis during BIR, and Pif1 is thought to help unwind the DNA in front polδ and also unwind the newly synthesized DNA strand from the template, thus allowing BIR DNA synthesis to occur within the context of a migrating DNA bubble-like structure ( Figure 5 E) [ 130 , 131 ].…”