Identification of the MMS22L-TONSL Complex that Promotes Homologous Recombination

Abstract

Budding yeast Mms22 is required for homologous recombination (HR)-mediated repair of stalled or broken DNA replication forks. Here we identify a human Mms22-like protein (MMS22L) and an MMS22L-interacting protein, NFκBIL2/TONSL. Depletion of MMS22L or TONSL from human cells causes a high level of double-strand breaks (DSBs) during DNA replication. Both proteins accumulate at stressed replication forks, and depletion of MMS22L or TONSL from cells causes hypersensitivity to agents that cause S phase-associated DSBs, such as topoisomerase (TOP) inhibitors. In this light, MMS22L and TONSL are required for the HR-mediated repair of replication fork-associated DSBs. In cells depleted of either protein, DSBs induced by the TOP1 inhibitor camptothecin are resected normally, but the loading of the RAD51 recombinase is defective. Therefore, MMS22L and TONSL are required for the maintenance of genome stability when unscheduled DSBs occur in the vicinity of DNA replication forks.

Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage

“…S2B). In this regard, TONSL is already known to participate in the repair of collapsed or stalled replication forks (Duro et al 2010;O'Connell et al 2010;O'Donnell et al 2010;Piwko et al 2010), which is also a known BRCA1 function (Pathania et al 2011;Schlacher et al 2012). However, as shown below, we found that TONSL may also participate in the response to transcription-associated damage.…”

Defects in homologous recombination repair behind the human diseases: FA and HBOC

“…These include RAD51AP1 (Wiese et al 2007) and TONSL/MMS22L (Duro et al 2010, O'Donnell et al 2010. Further analysis will shed more light on the possible interplay between these proteins and HR mechanisms underlying disorders like FA or HBOC.…”

Enhanced Killing of Cancer Cells by Poly(ADP-ribose) Polymerase Inhibitors and Topoisomerase I Inhibitors Reflects Poisoning of Both Enzymes

“…Second, a series of studies suggests a requirement for PARP1 to help resolve stalled replication forks (38,39), which are produced upon treatment with topo I poisons (16,17,40,41). Whether PARP1 acts by modulating WRN helicase (42,43) or recruiting MRE11 (39,44) or both is unclear.…”