SMARCAD1-mediated active replication fork stability maintains genome integrity

Abstract

The stalled fork protection pathway mediated by breast cancer 1/2 (BRCA1/2) proteins is critical for replication fork stability. However, it is unclear whether additional mechanisms are required to maintain replication fork stability. We describe a hitherto unknown mechanism, by which the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily-A containing DEAD/H box-1 (SMARCAD1) stabilizes active replication forks, that is essential to maintaining resistance towards replication poisons. We find that SMARCAD1 prevents accumulation of 53BP1-associated nucleosomes to preclude toxic enrichment of 53BP1 at the forks. In the absence of SMARCAD1, 53BP1 mediates untimely dissociation of PCNA via the PCNA-unloader ATAD5, causing frequent fork stalling, inefficient fork restart, and accumulation of single-stranded DNA. Although loss of 53BP1 in SMARCAD1 mutants rescues these defects and restores genome stability, this rescued stabilization also requires BRCA1-mediated fork protection. Notably, fork protection-challenged BRCA1-deficient naïve- or chemoresistant tumors require SMARCAD1-mediated active fork stabilization to maintain unperturbed fork progression and cellular proliferation.

Association between Mutation in SMARCAD1 and Basan Syndrome with Cutaneous Squamous Cell Carcinoma

“…It may be involved in dermatoglyph and sweat gland development by regulating the expression of epidermal differentiation-associated genes [ 16 ]. In addition, it also plays an import role in repairing potentially lethal DNA double-strand breaks [ 13 ] and maintaining genome integrity by stabilizing active replication [ 17 ]. Multiple studies have demonstrated that break points and mutations of the gene are involved in several human diseases, such as genodermatosis [ 5 , 18 , 19 ], malignant peripheral nerve sheath tumors [ 20 ], breast cancer [ 17 ], and pancreatic cancer [ 21 ].…”

Heat-induced SIRT1-mediated H4K16ac deacetylation impairs resection and SMARCAD1 recruitment to double strand breaks

“…No significant reduction in the IdU track could be observed, which would have been expected if the forks underwent degradation (Figures 5C and S5E). Together, these data suggest that heat stress impacts active, ongoing, and restarted replication fork stability (Lo et al, 2021) but not stalled fork protection (Schlacher et al, 2012). We have previously reported the involvement of MOF in suppression of replication stress (Singh et al, 2018) and, therefore, determined if MOF depletion and hyperthermia have a synergistic effect on replication stress.…”

R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

“…Interestingly, in fission yeast, Fft3 is shown to suppress histone turnover at heterochromatin regions to ensure the correct propagation of parental nucleosomes. Fft3 was further shown to suppress histone turn-over at difficult-to-replicate regions in order to preclude RNA:DNA hybrid formation that can lead to impaired fork progression [176]. It was suggested that in absence of Fft3, the enhanced turn-over leads to an open chromatin structure that facilitates R-loop formation at specific loci of the genome, especially those that are highly transcribing and/ or contain intragenic repetitive sequences [176].…”

“…More recently SMARCAD1 is shown to mediate a novel pathway of active replication fork stability by maintaining PCNA homeostasis at forks, distinct from BRCA-mediated stalled fork protection pathway [176]. Given that many of the factors discussed, apart from having a role in DNA breaks repair also have a role in replication fork stability and remodeling pathways [176,[236][237][238][239][240][241], it is possible that chromatin remodelers such as SMARCAD1 could have a role in the resolution of R-loops, as previously suggested in the fission yeast ortholog Fft3 [175]. Moreover, since SMARCAD1 travels with the replisome, its action could regulate R-loop resolution ahead of the fork, an interesting possibility that is yet to be tested.…”