Abstract
Disrupted DNA damage signaling greatly threatens cell integrity and plays significant roles in cancer. With recent advances in understanding the human genome and gene regulation in the context of DNA damage, chromatin biology, specifically biology of histone post-translational modifications (PTMs), has emerged as a popular field of study with great promise for cancer therapeutics. Here, we discuss how key histone methylation pathways contribute to DNA damage repair and impact tumorigenesis within this context, as well as the potential for their targeting as part of therapeutic strategies in cancer.
Highlights
THE ACCIDENT SCENESince the discovery of DNA by Swiss scientist Friedrich Miescher in 1869, numerous researchers have expanded on his work and contributed to our understanding of how genetic information was encoded, preserved, and stably transmitted across generations by DNA (Ciccia and Elledge, 2010)
Histone methyltransferases have long been established as critical players in gene transcription, expression regulation, DNA damage repair, and many more processes instrumental to cell integrity and normal physiology
We reviewed prominent histone methylation marks involved in DNA damage response (DDR) pathways and the potential of their respective small molecule inhibitors as not just therapeutic targets, and probes for further elucidating histone methyltransferases (HMTs) functions in cancer epigenetic regulation
Summary
When DNA lesions remain unrepaired, they may accumulate and block DNA replication progression, resulting in doublestranded breaks (DSBs) that are more difficult to repair and far more toxic (Khanna and Jackson, 2001; Jackson and Bartek, 2009). Previous studies by Chitale and Richly reported the collaboration between NSD2 and the endonuclease DICER, which facilitates heterochromatin formation and generates small non-coding RNAs that include the sequence of the damaged locus (Chitale and Richly, 2018) They later reported a mechanism by which NSD2 relocates to chromatin in a DICER-dependent manner and sets the stage for H4K20me to recruit XPA, a protein that binds to damaged DNA and acts as a scaffold for other repair proteins, at sites of UV lesions for genome-wide NER (Thoma, 1999; Pei et al, 2011; Chitale and Richly, 2018). Depletion of DOT1L methyltransferase activity after SGC0946 and EPZ-5676 treatments leads to an impaired DNA damage response indicated by decreased γH2AX levels as well as defective HR-mediated DSB repair without affecting NHEJ in colorectal cancer cell lines (Kari et al, 2019).
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