Recql5 and Blm RecQ DNA Helicases Have Nonredundant Roles in Suppressing Crossovers

Abstract

In eukaryotes, crossovers in mitotic cells can have deleterious consequences and therefore must be suppressed. Mutations in BLM give rise to Bloom syndrome, a disease that is characterized by an elevated rate of crossovers and increased cancer susceptibility. However, simple eukaryotes such as Saccharomyces cerevisiae have multiple pathways for suppressing crossovers, suggesting that mammals also have multiple pathways for controlling crossovers in their mitotic cells. We show here that in mouse embryonic stem (ES) cells, mutations in either the Bloom syndrome homologue (Blm) or the Recql5 genes result in a significant increase in the frequency of sister chromatid exchange (SCE), whereas deleting both Blm and Recql5 lead to an even higher frequency of SCE. These data indicate that Blm and Recql5 have nonredundant roles in suppressing crossovers in mouse ES cells. Furthermore, we show that mouse embryonic fibroblasts derived from Recql5 knockout mice also exhibit a significantly increased frequency of SCE compared with the corresponding wild-type control. Thus, this study identifies a previously unknown Recql5-dependent, Blm-independent pathway for suppressing crossovers during mitosis in mice.

RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments

“…It also suggests that the main function of Recql5 with respect to suppressing SCEs does not lie at the dissolution of DHJ, a deduction that is consistent with our previous finding that Blm and Recql5 have nonredundant roles in suppressing SCEs in mitotic cells (Hu et al 2005). …”

“…Therefore, while BLM likely represents the Sgs1 ortholog, the other RECQ-like helicases represent potential candidates as the functional equivalent of Srs2 in humans. We recently reported that mouse cells deficient in the RECQL5 homolog Recql5 exhibit an elevated level of SCEs, thus implicating this helicase in the regulation of HR (Hu et al 2005). Importantly, deletion of both Recql5 and Blm further increases the SCE frequency, consistent with Recql5 acting to regulate SCEs in mitotic cells via a mechanism that is distinct from Blm, perhaps by functioning similarly to Srs2 to suppress the channeling of DNA lesions into HR.…”

“…As Blm and Recql5 have nonredundant roles in suppressing SCEs in mitotic cells (Hu et al 2005), our finding that Recql5 knockout mice are highly cancer prone suggests that misregulation of HR may be the underlying basis for the cancer phenotype in these animals. Mutations in both human BLM and mouse Blm result in elevated rates of LOH and engender cancer susceptibility (German 1993;Luo et al 2000;Goss et al 2002;Hickson 2003).…”

RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability

“…RECQ5 is important for preventing both transcription-associated DSBs and DSBs induced by TOP1 poisons, such as camptothecin (CPT) [15][16][17] . The increased DSB formation observed in Recq5-deficient cells may contribute to elevated frequencies of homologous recombination and genome rearrangements 12,16 .…”

“…RECQ5 is important for preventing both transcription-associated DSBs and DSBs induced by TOP1 poisons, such as camptothecin (CPT) [15][16][17] . The increased DSB formation observed in Recq5-deficient cells may contribute to elevated frequencies of homologous recombination and genome rearrangements 12,16 . RECQ5 prevents transcription-associated DSBs by suppressing RNAPII-dependent transcription initiation 18 , and this may be achieved by the interaction between RNAPII and the RECQ5 KIX domain, which blocks the binding of transcription elongation factor TFIIS to RNAPII 19 .…”