Break‐induced replication links microsatellite expansion to complex genome rearrangements

Abstract

The instability of microsatellite DNA repeats is responsible for at least forty neurodegenerative diseases. Recently, Mirkin and colleagues presented a novel mechanism for microsatellite expansions based on break-induced replication (BIR) at sites of microsatellite-induced replication stalling and fork collapse. The BIR model aims to explain single-step, large expansions of CAG/CTG trinucleotide repeats in dividing cells. BIR has been characterized extensively in S. cerevisiae as a mechanism to repair broken DNA replication forks (single-ended DSBs) and degraded telomeric DNA. However, the structural footprints of BIR-like DSB repair have been recognized in human genomic instability and tied to the etiology of diverse developmental diseases; thus, the implications of the paper by Kim et al. extend beyond trinucleotide repeat expansion in yeast and microsatellite instability in human neurological disorders. Significantly, insight into BIR-like repair can explain certain pathways of complex genome rearrangements (CGRs) initiated at non-B form microsatellite DNA in human cancers.

Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants

“…The relationship between an altered chromatin structure and carcinogenesis has been described in our earlier work, which revealed the presence of alterations in the higher-order chromatin structure in histologically normal tissue that was adjacent to the tumor 40 . Additionally, Leffak 41 linked the amplification of repetitive sequences, which is the mechanism responsible for the development of numerous neurodegenerative diseases, to the repair of collapsed replication forks.…”

“…Mechanisms of how stalling DNA replication forks can promote either epigenetic or genetic changes were recently reviewed by Rowlands et al . 58 and Leffak 41 , respectively.…”

Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication

“…In this model system, break induced replication (BIR) has been shown to generate large scale repeat expansions and mutations at a distance, as seen in human tumors (36)(37)(38). BIR is also a consequence of replication stress in human cells (39)(40)(41)(42)(43)(44). Indeed in humans, replicationdependent single-ended DSBs (seDSBs) leading to BIR have been proposed to be responsible for copy number variation (CNV), several forms of GCR (19,43,45), oncogenesis (12)(13)(14)42,(46)(47)(48)(49) and multiple developmental disorders (27,28,47,(50)(51)(52)(53).…”

Asymmetric Processing of DNA Ends at a Double-Strand Break Leads to Unconstrained Dynamics and Ectopic Translocation

“…The budding yeast genome has relatively little interstitial repeat sequence and lacks centromeric satellite arrays. The introduction of internal repeats leads to replication fork stalling and both the expansion and reduction of the initial repeat (Kim and Mirkin, 2013;Leffak, 2017). Inserts of 120 bp of (TGTGTGGG) 15 can lead to gross chromosomal rearrangements, translocations, and acentric minichromosomes (Aksenova et al, 2013), yet how internal repeats influence break processing was never determined.…”

“…Collectively, repeats comprise up to 70% of the human genome (Padeken et al, 2015). While the functions served by repeats are unclear, it is unequivocally established that they are a source of genomic instability (Kim and Mirkin, 2013;Leffak, 2017). Replication-induced insertions, deletions, and breaks are enhanced at repeats, and spontaneous breaks within repeat elements compromise genome integrity, as they are prone to inappropriate translocations (Aksenova et al, 2013).…”