Essential roles for Pol delta in Pol theta mediated end joining

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Project summary (partly from overall specific aims of original proposal) Polymerase theta (Pol θ, gene name Polq) is essential in cancers deficient in BRCA1/2 – or indeed in cells deficient in any one of 140 different genes involved in DNA damage responses – yet its deficiency is well tolerated in most normal cells. As a consequence, targeted inhibition of Pol θ could be effective in as many of 20% of human cancers. To date, much remains unclear as to how this 290 kDa multi-domain and multi-activity enzyme contributes to its biological role, and how individual pathway steps are performed. We are addressing this knowledge gap in Aim 1; investigation of roles for Pol δ is performing pathways steps, which we initiate with the help of this supplement is essential to achieve this goal. We are additionally investigating the cellular contexts that engage Pol θ or TMEJ in Aim 2; 3 seeks to integrate insights gained from work performed in support of overall Aims 1 and 2 to develop rationales for safer, more effective therapies.