NuMA regulates DNA repair and transcription in response to oxidative stress

Cells are constantly exposed to various sources of stress that could cause DNA damage. One of the most common sources is oxidative stress, which leads to the formation of single-strand DNA breaks. These breaks are recognized and repaired by the cellular DNA repair machinery. Defects in the repair machinery has been implicated in cancer, neurological disorders, and ageing.

NuMA was recently identified in our laboratory as a novel player in the repair of oxidative DNA breaks. It is highly expressed in the cerebellum, which is vulnerable to oxidative stress, suggesting an important role in protecting neurons from oxidative DNA damage. The mechanisms by which NuMA promotes oxidative DNA repair and gene expression was largely unknown.

In this thesis, I established that NuMA protects promoters and enhancers from oxidative DNA damage. NuMA is enriched at these regions and facilitates the recruitment of single-strand break repair components such as TDP1 to promoters. Moreover, NuMA was found to regulate transcription following oxidative stress and promote the expression of a specific group of genes. It does so by facilitating the release of paused RNA Polymerase 2 (RNAPII) molecules from the promoter proximal pause regions. In response to oxidative stress, it limits the PARylation of RNAPII, thereby, increasing its availability at the promoters to facilitate transcription.

This work underlies the importance of nuclear structural proteins such as NuMA in the maintenance of genome integrity and gene expression.