. Author manuscript; available in PMC: 2021 Nov 1.

Published in final edited form as: DNA Repair (Amst). 2020 Aug 15;95:102943. doi: 10.1016/j.dnarep.2020.102943

Table 1. List of functions of SNF2-family fork remodelers exhibited in biochemical assays, cellular and animal models, and human disease.

Citations of papers describing the indicated functions of SMARCAL1, ZRANB3 and HLTF are included in the table.

	HLTF	SMARCAL1	ZRANB3
Biochemical Activities	Activities • Fork reversal and restoration [90,94,114,116,117,120] • D-loop formation [121] • Ubiquitin ligase activity [112,113] Substrate preference • DNA binding: ssDNA and fork substrates with 3’-OH overhang [116–119] • Fork reversal: fork substrate with 3’-OH available in the vicinity of the fork branch point [116,117]; fork with gap on leading or lagging strand [117] • Fork restoration: fork with lagging strand gap (final product) [117] Inhibition by • FANCJ [135]	Activities • Fork reversal and restoration [87,89,91–93,106,107,129] • D-loop dissolution [91] Substrate preference • DNA binding: ssDNA/dsDNA junction with 3’ or 5’ ssDNA overhangs, fork structures [93,293] • Fork reversal: fork substrate with a leading strand gap bound by RPA [92,107] • Fork restoration: fork with lagging strand gap bound by RPA (final product) [92] Association with • RPA2 [100,103,104] Stimulation by • RPA [92,107] Inhibition by • ATR [129] • MCM10 [294] • RAD52 [133]	Activities • Fork reversal and restoration [89,91,92,108,111] • D-loop dissolution [91] • Inhibition of D-loop formation [91] • ATP-dependent endonuclease activity [108,110,111] Substrate preference • DNA binding: fork structures [108,110] • Fork reversal: fork with gap on leading or lagging strand [92] • Fork restoration: fork with lagging strand gap (final product) [92] • Endonuclease activity: splayed duplex [108] Association with • PCNA and poly-ubiquitinated PCNA [91,108,109] Stimulation by • PCNA [110] (endonuclease activity) Inhibition by • RPA [92] (fork remodeling activity)
Cellular Functions	Functions • Fork reversal in response to replication stress [90] • Restart of stalled forks [94] • Suppression of PRIMPOL- and REV1-mediated restart of stalled forks [90] • Induction of PCNA polyubiquitination upon replication stress [112,113] • Stimulation of TLS [295,296] • Suppression of cellular resistance to HU [90,135] and MMC [90], promotion of cellular resistance to UV and MMS [112,113] • Suppression of replication stress-induced DSB formation [90] • Gene expression regulation [297,298] BRCA1/2-deficient cells • Promotion of replication stress-induced fork degradation and DSB formation [89] FANCJ-deficient cells • Promotion of replication stress-induced fork degradation and suppression of DSB formation [135] • Promotion of MMC sensitivity and HU resistance [135]	Functions • Fork reversal in response to replication stress [87,89,93] • Restart of stalled forks [100] • Telomere maintenance in ALT [123,125,215] and non-ALT cells [124] and ALT suppression [124,187] • Stimulation of NHEJ [299] • Promotion of cellular resistance to HU, aphidicolin, MMC, IR and camptothecin [100,101,103,197,299] • Suppression of DNA damage formation [100,101,103,124,300] • Gene expression regulation in response to replication stress and heat shock [300–305] BRCA1/2-deficient cells • Promotion of replication stress-induced fork degradation [89] • Induction of DNA damage [159], replication stress-induced DSB formation and genomic rearrangements [89] • Suppression of cellular resistance to replication stress-inducing agents in breast cancer cells, but not in mammary epithelial cells [89] • Suppression of PRIMPOL-mediated restart of stalled forks [201] Myc-overexpressing cells • Promotion of replication fork progression and suppression of fork collapse [196]	Functions • Fork reversal in response to replication stress [86] • Restart of stalled forks [91,109] • Recognition of poly-ubiquitinated PCNA [91,108] • Suppression of hyper-recombination [91] • Promotion of cellular resistance to camptothecin, HU, cisplatin, MMC [91,109] and MMS [108] BRCA1/2-deficient cells • Promotion of replication stress-induced fork degradation [89,96] • Induction of replication stress-induced DSBs and genomic rearrangements in mammary epithelial cells [89]; suppression of genomic rearrangements in U2OS cells [96] Myc-overexpressing cells • Promotion of replication fork progression and suppression of fork collapse [196] β-cells • Promotion of insulin secretion in response to glucose [179]
Mouse Models	Hltf ^del/del • Semi-lethal / neonatal lethal (deletion of exons 11–12) [297,298,306] or exhibiting normal development, fertile, and normal life span (deletion of exons 1–5) [183] • Formation of carcinogen-induced colorectal cancer [306] Apc^min/+ • Hltf deletion increases intestinal adenocarcinoma invasion and malignancy [183]	Smarcal1^del/del • No developmental, growth, or physical abnormalities [305] • Reduced B-cell count [196,305] • Reduced growth and weight and albuminuria upon RNA pol II inhibition [305] • Hypersensitivity to campothecin, etoposide, and HU [301] • Increased survival, delayed T-cell lymphomagenesis, impaired T-lymphocyte reconstitution after IR [197] Eµ-myc transgenic mice • Smarcal1^del/+, but not Smarcal1^del/del, mice exhibit increased myc-induced B-cell lymphomagenesis and decreased survival [196]	Zranb3^−l− • No abnormalities [196] Eµ-myc transgenic mice • Loss of one or both Zranb3 alleles inhibits myc-induced B-cell lymphomagenesis [196]
Human Disease	Cancer • Frequently silenced in colorectal and gastric cancers [181,182] • Overexpressed in esophageal, uterine, and squamous cell carcinoma [184] • Overexpression is associated with increased metastasis and poorer prognosis in non-small cell lung cancer [185]	Genetic syndrome • Biallelic mutations cause Schimke immuno-osseous dysplasia (SIOD) [174,175,178,305,307] Cancer • Mutations identified in glioblastoma carrying wildtype TERT promoter and IDH1/2 genes, and ALT-positive [187]	Genetic syndrome • Mutations associated with African-specifc type-2 diabetes [179] Cancer • Candidate tumor suppressor in endometrial cancer [186] • Mutations associated with carcinosarcoma [308]