The SNM1B/APOLLO DNA nuclease functions in resolution of replication stress and maintenance of common fragile site stability

Abstract

SNM1B/Apollo is a DNA nuclease that has important functions in telomere maintenance and repair of DNA interstrand crosslinks (ICLs) within the Fanconi anemia (FA) pathway. SNM1B is required for efficient localization of key repair proteins, such as the FA protein, FANCD2, to sites of ICL damage and functions epistatically to FANCD2 in cellular survival to ICLs and homology-directed repair. The FA pathway is also activated in response to replication fork stalling. Here, we sought to determine the importance of SNM1B in cellular responses to stalled forks in the absence of a blocking lesion, such as ICLs. We found that depletion of SNM1B results in hypersensitivity to aphidicolin, a DNA polymerase inhibitor that causes replication stress. We observed that the SNM1B nuclease is required for efficient localization of the DNA repair proteins, FANCD2 and BRCA1, to subnuclear foci upon aphidicolin treatment, thereby indicating SNM1B facilitates direct repair of stalled forks. Consistent with a role for SNM1B subsequent to recognition of the lesion, we found that SNM1B is dispensable for upstream events, including activation of ATR-dependent signaling and localization of RPA, γH2AX and the MRE11/RAD50/NBS1 complex to aphidicolin-induced foci. We determined that a major consequence of SNM1B depletion is a marked increase in spontaneous and aphidicolin-induced chromosomal gaps and breaks, including breakage at common fragile sites. Thus, this study provides evidence that SNM1B functions in resolving replication stress and preventing accumulation of genomic damage.

Identifying Putative Susceptibility Genes and Evaluating Their Associations with Somatic Mutations in Human Cancers

“…DCLRE1B, encoding a 5ʹ-3ʹ exonuclease, has been reported to play a vital role in DNA double-strand break (DSB) repair by affecting efficient localization of BRCA1 and the MRE11/RAD51/NBS1 complex. 76 GATAD2A, encoding a subunit of the nucleosome remodeling and histone deacetylase (NuRD) complex, plays an important role in recruiting NuRD to the sites of damaged chromatin for repair of DSBs by homologous recombination. 35,[77][78][79] Interestingly, we also found that a low expression level of ESR1 was associated with an increase of TMB of cancer-driver genes.…”

Are common fragile sites merely structural domains or highly organized “functional” units susceptible to oncogenic stress?

“…Required for fork repair and resolving UFBs [ 41 , 50 ] PICH PICH (Plk1 interacting checkpoint) is a helicase/translocase involved in resolving UFBs in mitosis [ 49 ] SNM1B/APOLLO A nuclease component of the FA pathway involved in homology-directed repair. Also facilitates DNA localization of FANCD2 and BRCA1 [ 86 ] Rad51 Component of the HR pathway involved in DSB repair and HJ mediated RF restart [ 47 ] DNA-PKcs NHEJ pathway component [ 47 ] Ligase IV NHEJ pathway component [ 47 ] …”

Updating the mechanisms of common fragile site instability: how to reconcile the different views?

“…Two recent works [ 37 , 38 ] reported that the endonucleases MUS81/EME1 and ERCC1, which contribute to processing a wide variety of DNA structures such as stalled forks and Holliday junctions, are involved in the maintenance of CFSs during mitosis. SNM1B/APOLLO, a nuclease involved in the FANC pathway, also contributes to stabilizing CFSs [ 39 ]. Together, these results strongly suggest that segregation of incompletely replicated chromosomes can still be rescued through accurate processing of non-replicated DNA and that formation of 53BP1 bodies favors faithful repair and/or replication completion in the next cell cycle.…”