Fig. 7: G9a overexpression correlates with poor prognosis in ovarian cancer, highlighting the importance of a timely accumulation of de novo H3K9me1/2/3 marks and its disassembly catalysed by ‘writers’ and ‘erasers’ at stressed replication forks to maintain fork stability.

a,b, Combined mean expression was calculated to distinguish TCGA patients with ovarian cancer with low or high GLP/G9a expression^71,95,96. Kaplan–Meier curves were generated against progression-free survival (a) and overall patient survival (b) (n = 614 patients). P values were calculated with the use of a two-sided log-rank test. c, G9a/EHMT2 associated with replication forks is activated by canonical DNA replication checkpoint pathway to catalyse H3K9me1/me2 at replication forks upon replication stress. Activated G9a generates a platform of H3K9me1/me2/me3 in concert with Suv39h1 at the site of stressed replication forks, which subsequently recruits histone deacetylase, HDAC1 to deacetylate the nucleosomes. Such closed chromatin conformation may create a protective compaction bubble that protects replication forks by (1) promoting efficient recruitment of fork protection factors, BARD1-BRCA1; and (2) such a conformation may also prevent the access to DNA nucleases and other detrimental factors, such as PRIMPOL that can lead to accumulation of ssDNA gaps behind the replication forks. Furthermore, synergistic activity of G9a and Suv39h1 further prevents the substrate, H3K9me1/me2 nucleosomes, availability to H3K9-demethylase, JMJD1A/KDM3A, timely assembly of which facilitates the disassembly of heterochromatin to promote their fork restart. Figure created with biorender.com. Source numerical data are available in Source Data.