Posttranslational modifications (PTMs), occurring on various histones and nonhistone proteins, greatly enrich the diversity of the proteome, thereby profoundly affecting protein structures and biological functions. Histones are particularly important components of genomic chromatin and their modifications represent a critical event in the control of DNA damage response (DDR) induced by endogenous or exogenous insults. Extensive studies have revealed the roles of classical PTMs including phosphorylation, acetylation and ubiquitination, in modulating chromatin dynamics through the recruitment of chromatin remodeling complex and repair machinery during DDR process, thus successfully maintaining genome stability and preventing the cells from adverse fates such as apoptosis or malignant transformation. In recent years, several novel PTMs, such as ufmylation, crotonylation, succinylation and lactylation, have been discovered on both histones and nonhistone proteins. Their potential roles and regulatory mechanisms during DDR process have indeed emerged, but are still far from completely understood. This review primarily focuses on the regulation of novel PTMs in DDR, and further discusses the repair networks of cell in response to DNA damage and the interplay between diverse modifications in DNA damage response, which aims to expand the understanding of PTMs involved in DDR regulation and provides potential insights into disease intervention.