SMARCAL1, the annealing helicase and the transcriptional co‐regulator

Abstract

The ATP‐dependent chromatin remodeling proteins play an important role in DNA repair. The energy released by ATP hydrolysis is used for myriad functions ranging from nucleosome repositioning and nucleosome eviction to histone variant exchange. In addition, the distant member of the family, SMARCAL1, uses the energy to reanneal stalled replication forks in response to DNA damage. Biophysical studies have shown that this protein has the unique ability to recognize and bind specifically to DNA structures possessing double‐strand to single‐strand transition regions. Mutations in SMARCAL1 have been linked to Schimke immuno‐osseous dysplasia, an autosomal recessive disorder that exhibits variable penetrance and expressivity. It has long been hypothesized that the variable expressivity and pleiotropic phenotypes observed in the patients might be due to the ability of SMARCAL1 to co‐regulate the expression of a subset of genes within the genome. Recently, the role of SMARCAL1 in regulating transcription has been delineated. In this review, we discuss the biophysical and functional properties of the protein that help it to transcriptionally co‐regulate DNA damage response as well as to bind to the stalled replication fork and stabilize it, thus ensuring genomic stability. We also discuss the role of SMARCAL1 in cancer and the possibility of using this protein as a chemotherapeutic target.

Widespread impact of nucleosome remodelers on transcription at cis-regulatory elements

“…Our findings support the regulatory paradigm that CHD4, BRG1, p400, and SNF2H act as key contributors to the mRNA transcriptome in ES cells, as demonstrated in previous studies 4,5,9,41,42,95 , with more modest, but still critical, contributions from CHD1, INO80, CHD8, SRCAP, and BTAF1 7,8,13,43,44,53 (Figure 1). Our study also demonstrates that multiple additional remodelers have modest contributions to mRNA transcriptional regulation in ES cells, including SMARCAL1, HLTF, and SHPRH, consistent with prior work where loss of each of these ATPases has been associated with effects on mRNA transcription in other systems 33,35,40,59,96,97 .…”

“…Many remodelers are recruited to enhancers and promoters to regulate gene expression 7,13,[31][32][33][34][35][36][37][38][39][40][41][42][43] ; however, only a handful have been shown to play a direct role in ncRNA production at CREs 44,45 . esBAF suppresses the production of eRNAs and uaRNAs at target CREs by maintaining the positioning of adjacent nucleosomes 46 .…”

The Biochemical Mechanism of Fork Regression in Prokaryotes and Eukaryotes—A Single Molecule Comparison

“…The human homolog was subsequently purified from HeLa cells and was initially called Hep-A-related protein or HARP due to its sequence similarity to the prokaryotic HepA protein [ 79 ]. Subsequent sequence analysis revealed homology to the ATP-dependent chromatin remodelers, resulting in the redesignation of the enzyme as SMARCAL1 [ 80 ]. In vitro studies have gone on to show that the ATPase activity is also stimulated by fork DNA structures and is an ATP-dependent annealing enzyme, although the authors called SMARCAL1 an ATP-dependent annealing helicase, which is not only confusing but misleading, as it cannot strand-separate, i.e., it has no helicase activity [ 81 , 82 , 83 ].…”

“…Even more confusing is the classification of SMARCAL1 as a chromatin remodeler, as to date this activity has not been associated with the protein. Instead, it is also thought of as a transcription co-regulator [ 80 ].…”

Chromatin-remodeling factor CHR721 with non-canonical PIP-box interacts with OsPCNA in Rice

“…In humans, ZRANB3 is most closely related to the SIOD disorder protein SMARCAL1, and they both belong to the same subfamily with 44% identity [4,5]. SMARCAL1 can be recruited to the DNA damage site by the single-stranded binding protein, RPA, and help to reanneal stalled replication forks [1,3]. In rice, the closely related gene of ZRANB3 by blasting the amino acids were CHR721 and CHR726, which all belong to the SMARCAL1 subfamily, but no typical NZF-type zinc finger was detected.…”