RECQ1 Helicase Interacts with Human Mismatch Repair Factors That Regulate Genetic Recombination*[boxs]

Abstract

Understanding the molecular and cellular functions of RecQ helicases has attracted considerable interest since several human diseases characterized by premature aging and/or cancer have been genetically linked to mutations in genes of the RecQ family. Although a human disease has not yet been genetically linked to a mutation in RECQ1, the prominent roles of RecQ helicases in the maintenance of genome stability suggest that RECQ1 helicase is likely to be important in vivo. To acquire a better understanding of RECQ1 cellular and molecular functions, we have investigated its protein interactions. Using a co-immunoprecipitation approach, we have identified several DNA repair factors that are associated with RECQ1 in vivo. Direct physical interaction of these repair factors with RECQ1 was confirmed with purified recombinant proteins. Importantly, RECQ1 stimulates the incision activity of human exonuclease 1 and the mismatch repair recognition complex MSH2/6 stimulates RECQ1 helicase activity. These protein interactions suggest a role of RECQ1 in a pathway involving mismatch repair factors. Regulation of genetic recombination, a proposed role for RecQ helicases, is supported by the identified RECQ1 protein interactions and is discussed.

Mismatch Repair during Homologous and Homeologous Recombination

“…In addition, HsBLM interacts with HsMLH1 and HsExoI and, in conjunction with TopIIIa and both RMI1and RM2, has been shown to dissolve double Holliday junctions (Langland et al 2001;Pedrazzi et al 2003;Wu and Hickson 2003;Nimonkar et al 2011). HsRECQ1 (Doherty et al 2005) and HsWRN (Saydam et al 2007) also interact with HsMLH1, and HsRECQ1 as well as with HsExoI (Cui et al 2004). Furthermore, purified HsRECQ1 forms a subnanomolar affinity complex with HsMSH2-HsMSH6, and HsMSH2-HsMSH6 stimulates HsRECQ1 helicase activity on the 3 0 -flap structures (Doherty et al 2005).…”

“…4; Table 1). Among the five known human RecQ family helicases, three, HsRECQ1 (Doherty et al 2005), HsBLM (Pedrazzi et al 2003), and HsWRN (Saydam et al 2007), have been shown to interact with the HsMSH2-HsMSH6 heterodimer. HsBLM and HsWRN also interact with the HsMSH2-HsMSH3 heterodimer (Pedrazzi et al 2003;Saydam et al 2007).…”

DNA Mismatch Repair Gene Polymorphisms Affect Survival in Pancreatic Cancer

“…MGMT repairs the O(6)-alkyl-guanine mismatches dependent on MutS␣/MutL␣/EXO1 [13,14]. MutS␣ stimulates RECQL helicase activity; RECQL stimulates EXO1 incision activity and interacts with MLH1 [16]. 62 replication, recombination, and repair [16,17].…”

“…MutS␣ stimulates RECQL helicase activity; RECQL stimulates EXO1 incision activity and interacts with MLH1 [16]. 62 replication, recombination, and repair [16,17]. TP73, a member of the p53 family, is involved in cellular responses to stress and development [18].…”

RECQL: a new breast cancer susceptibility gene

“…Interestingly, RAD51-mediated replication fork reversal induced by sublethal genotoxic treatment with agents that interfere with the normal progression of replication is antagonized by poly (ADP-ribose) polymerase (PARP)/ RECQL-regulated restart, 26 leading us to speculate that the direct interaction between RECQL and RAD51 27 may affect their cross-talk at stalled replication forks. RECQL was also found to physically and functionally interact with mismatch repair factors that are implicated in cancer suppression, 28 which is likely to be important for the mechanism(s) whereby RECQL regulates genetic recombination to suppress DNA damage and chromosomal instability. 27,29 …”