MutSβ Stimulates Holliday Junction Resolution by the SMX Complex

Abstract

Highlights d MutSb, but not MutSa, interacts directly with SLX4 d MutSb stimulates the resolution of recombination intermediates by SMX d Defects in MutSb lead to the accumulation of unresolved anaphase bridges at mitosis d MutSb is required for efficient Holliday junction resolution and genome stability

SLX4 dampens MutSα-dependent mismatch repair

“…Besides inhibition of MMR, an alternative explanation for how SLX4 mediates 6-TG and MNNG resistance could have been through the resolution of HR intermediates formed after MutSa-dependent MMR. In line with this, cells lacking BRCA2 or RAD51 paralogs were previously shown to be hypersensitive to 6-TG or MNNG (59)(60)(61)(62) and MutSb stimulates in vitro the processing of HR intermediates by the SMX complex (26). However, MSH3-deficient cells are not sensitive to 6-TG nor MNNG making this an unlikely explanation (50)(51)(52)(53).…”

“…Hence, SLX4 exerts multiple functions in genome maintenance, each mediated by one or several protein-protein interactions. Intriguingly, the mismatch repair (MMR) factor MSH2 was also identified as a binding partner of human SLX4 (3) but the functional relevance of this interaction remained unexplored until recently (26). The primary role of MMR is to correct replication errors introduced by DNA polymerases.…”

“…Immunoprecipitation of overexpressed SLX4 coupled to mass spectrometry (IP-MS) analyses suggested that it associates with MutSb (3), MutSa (33) or both complexes (34). Noteworthy, interaction between SLX4 and MutSb, but not MutSa, was shown to stimulate HJ resolution by the SLX4-SLX1 and SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX) HJ resolvase complexes in vitro (26). Furthermore, co-depletion of MSH3 and SLX4 did not further exacerbate the phenotypes associated with the reduced processing of recombination intermediates caused by depleting SLX4 alone, suggesting that SLX4 and MutSb also collaborate in vivo (26).…”

Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

“…Recent work has also shed light on the interaction between SLX4 and the MSH2-MSH3 heterodimer ( Figure 5A ), which has important roles in mismatch repair and homologous recombination ( Svendsen et al, 2009 ; Gonzalez-Prieto et al, 2015 ; Zhang et al, 2019 ; Young et al, 2020 ). Coimmunoprecipitation experiments showed that the interaction between SLX1-SLX4 and MSH2-MSH3 is consistent throughout the cell cycle, suggesting that MSH2-MSH3 may represent an integral component of the SX and SMX complexes ( Young et al, 2020 ). Indeed, MSH2-MSH3 stimulated the ability of SLX1-SLX4 and SMX to cleave Holliday junctions and trinucleotide repeat loops, expanding the repertoire of DNA substrates that are cleaved by SLX4-nuclease complexes ( Young et al, 2020 ).…”

“…Coimmunoprecipitation experiments showed that the interaction between SLX1-SLX4 and MSH2-MSH3 is consistent throughout the cell cycle, suggesting that MSH2-MSH3 may represent an integral component of the SX and SMX complexes ( Young et al, 2020 ). Indeed, MSH2-MSH3 stimulated the ability of SLX1-SLX4 and SMX to cleave Holliday junctions and trinucleotide repeat loops, expanding the repertoire of DNA substrates that are cleaved by SLX4-nuclease complexes ( Young et al, 2020 ). The interplay between SLX4 and MSH2-MSH3 was reviewed recently ( Young and West, 2021 ).…”