Repeat expansions confer WRN dependence in microsatellite-unstable cancers

Abstract

The RecQ DNA helicase WRN is a synthetic lethal target for cancers with microsatellite instability (MSI), a form of genetic hypermutability arising from impaired mismatch repair 1-4 . WRN depletion induces widespread DNA double strand breaks (DSBs) in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI cancers from DSBs remains unclear. Here, we demonstrate that TAdinucleotide repeats are highly unstable in MSI cells and exhibit surprisingly large-scale expansions, distinct from previously described insertion/deletion mutations of a few nucleotides 5 . We show that expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and necessitate unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to MUS81 nuclease cleavage, leading to massive chromosome shattering. Thus, our study uncovers a distinct biomarker within MSI tumors that underlies the synthetic lethal dependence on WRN, thereby supporting the development of WRN-based therapeutics.

Human MUS81: A Fence-Sitter in Cancer

“…Considering the vulnerabilities of MSI, WRN is identified as an essential gene in MSI cells (Chan et al, 2019). WRN depletion causes DSBs and chromosome shattering (van Wietmarschen et al, 2020) and reduces the cell viability (Chan et al, 2019) in MSI cells but neither in microsatellite stable (MSS) cancer cells nor in primary human cells. However, MUS81 exhaustion before WRN depletion notably cuts down the chromosome shattering and DSBs formation at TA repeats (van Wietmarschen et al, 2020), indicating that MUS81 cleavage contributes to apoptosis of MSI cells with WRN deficiency (Figure 2).…”

“…In MSI cells, TA repeats, which are highly unstable, encounter and accumulate large-scale expansions for some reason (van Wietmarschen et al, 2020). Cruciform structures form at the expanded TA repeats (Inagaki et al, 2009), which are tended to stall replication forks.…”

“…For instance, endonuclease activity of MUS81 is crucial for survival of BRCA2-insufficient cancer cells (Lai et al, 2017;Lemaçon et al, 2017). Nevertheless, in WRN-depleted microsatellite instability (MSI) cancer cells, MUS81 complex shatters chromosomes, which causes apoptosis of cancer cells (van Wietmarschen et al, 2020).…”

Human RecQ Helicases in DNA Double-Strand Break Repair

“…Hence, it would be promising to investigate posttranslational modifications of RecQ helicases with the combination of spatial and temporal factors as well as stresses. Recently, WRN was identified as a synthetic lethal vulnerability in cancers with microsatellite instability (Chan et al, 2019;van Wietmarschen et al, 2020). Interestingly, CPT treatment leads to the degradation of WRN (Shamanna et al, 2016a;Li et al, 2020), suggesting that cancers with microsatellite instability may be a candidate target for CPT treatment to drive WRN-specific vulnerable tumors.…”

Special Issue: DNA Repair and Somatic Repeat Expansion in Huntington’s Disease

“…Over 50 human genetic disorders are caused by an expanded tandem repeat tract, in a variety of repeats in both coding and non-coding sequences across the genome [11]. New methods are demonstrating that there are likely to be many more repeat expansion loci that have clinical associations [12,13]. Available evidence points to the involvement of DNA repair proteins, whose activities underlie repeat length alterations for at least some of these diseases [14][15][16].…”