TABLE 1.
The roles of histone variants and modifications in replication stress.
| Histone variant/modification | Chaperone/enzyme | Functions in replication stress | Reference(s) |
|---|---|---|---|
| H2A.X | — | Phosphorylation at serine-139 (γH2AX) by ATM/ATR is an early marker of damage and involved in repairing replicative lesions in checkpoint-blind yeast | Ward and Chen (2001), Redon et al. (2003), Sirbu et al. (2011), Lyu et al. (2019), Saldivar et al. (2018) |
| γH2AX maintains normal S/G2 phase transition during unperturbed replication | |||
| macroH2A | FACT | Promotes HR factor recruitment to stressed forks and persists at fragile sites after replication stress resolution to protect from future replication stress | Kim et al. (2018) |
| LSH | Promotes HR factor recruitment to stressed forks | Xu et al. (2021) | |
| Depletion causes increased H4K20me2, which supresses fork protection | |||
| — | Protects the inactive X chromosome from replication stress | Sebastian et al. (2020) | |
| H2A.Z (Htz1) | SWR-C | Prevents misincorporation on dNTPs and collapse of stalled replication forks | Van et al. (2015), Srivatsan et al. (2018) |
| CENP-Α | HJURP | Suppresses formation of centromeric R-loops to prevent TRCs | Giunta et al. (2021) |
| H2A K13/K15 Ub | RNF168 | Facilitates normal S phase progression and promotes fork restart | Schmid et al. (2018); Nakamura et al. (2021) |
| H2B K123Ub | Bre1 (yeast) | Stabilises nucleosomes on newly replicated DNA an facilitates fork progression | Trujillo and Osley (2012), Lin et al. (2014), Northam and Trujillo (2016), Hung et al. (2017) |
| Activates the intra-S phase checkpoint | |||
| Maintains error-free DNA damage tolerance | |||
| H3K4me1/me3 | MLL3/4 | Promotes MRE11-depedendent fork degradation in BRCA-deficient cells | Ray Chaudhuri et al. (2016) |
| SETD1A | Promotes RAD51-mediated fork protection through H3.1 chaperoning | Higgs et al. (2018) | |
| Set1 (yeast) | Prevents TRCs in active regions | Chong et al. (2020) | |
| H3K9me2/me3 | Met-2, set-25 (C. elegans) | Represses genes in repetitive regions to prevent R-loop formation | Zeller et al. (2016) |
| H3K27me3 | EZH2 | Recruits MUS81 to facilitate fork restart | Rondinelli et al. (2017) |
| H4K20me1/me3 | PR-Set7 | Prevents replication stress by controlling fork number and velocity | Jørgensen et al. (2007a), Tardat et al. (2007), Saredi et al. (2016) |
| H4K20me0 on new histones provides binding site for TONSL-MMS22L to facilitate post-replicative repair | |||
| H4 K5/K12 ac | HAT1 | Prevents replication stress and protects stressed forks from MRE11-dependent degradation | Nagarajan et al. (2013), Agudelo Garcia et al. (2020) |
| H4K8ac | PCAF | Promotes MRE11- and EXO1-dependent degradation of stalled forks in BRCA2-deficient cells | Kim et al. (2020) |