The DNA damage response (DRR) is an integrated series of pathways that dictate the cellular response to DNA damage and replication stress. The DDR is actively being pursued therapeutically to treat cancer and the majority of activity in the arena involves targeting the PI3 kinase-like kinases (PIKKS) ATM ATR and DNA-PK. However, the majority of proteins involved in DNA repair and the DDR are not kinases and these non-PIKK proteins represent an important area of investigation. There has been considerable attention to these non-PIKK targets as novel mechanisms to impinge on the DDR and DNA repair to treat cancer.

The PIKK’s as targets dominate the DDR therapeutic landscape and there are reviews of the latest advances and clinical trials appearing daily. An authoritative review of the non-PIKKs targets in DDR and DNA repair does not exist. In this collection of articles, we envision a series of primary research articles and select reviews spanning the cadre of pathways and proteins that look beyond PIKK targeted cancer therapeutics. The development of small molecule chemical inhibitors has been critical to advancing our understanding of nearly all biochemical pathways. Non-PIKK targeted DNA repair and DDR agents have also contributed to our understanding and we envision a subset of the articles will focus on the biochemical mechanisms elucidated using these novel agents and highlight the innovative techniques and approaches used to develop such molecules. Finally, to bring it all together, we envision a small number of articles highlighting how non-PIKK targets can be incorporated into specific therapeutic treatment regimens.

This Research Topic focuses on publishing Original Research and Review articles focusing on, but not limited to the following:

- Different classes or pathways of non-PIKK. These could include direct repair inhibitors, BER, NER, HR, NER, NHEJ and MMR inhibitors.
- Unique mechanisms of action including protein-protein and protein-DNA interactions inhibitors.
- The latest advances in some of the specific protein targets. These could include, APE1, MTH1, Rad51, pol B, Fen1, pol eta, theta and kappa, Ku, RPA and XPF.

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Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.

The Topic Editors declare the following commercial or financial relationships: Dr Turchi is a cofounder, holds shares and receives research grants from NERx Biosciences. He also is an the inventor on patents concerning DDR inhibitors. Dr Pawelczak is the Vice President of Research at NERx Biosciences and holds shares in the company. Dr. Weinfeld holds several patents for DNA repair inhibitors through the University of Alberta. Dr. McHugh's laboratory receives funding from Pfizer.

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