The accumulation of DNA damage can lead to the introduction of genetic mutations and an increase in genomic instability. Genomic instability is associated with several human diseases including cancer and neurodegenerative diseases. Emerging evidence suggests that non-coding RNA pathways contribute to maintaining genome stability. One such non-coding RNA pathway is the PIWI/piRNA pathway. The PIWI family of proteins is a subfamily of Argonaute proteins and is involved in the biogenesis of small non-coding RNAs termed piRNAs (Piwi interacting RNAs) in a Dicer independent fashion. The PIWI/piRNA pathway is known to suppress gene expression through posttranscriptional and epigenetic modifications. Recently the PIWI/piRNA pathway has been implicated in helping to maintain genome integrity. Specifically, Drosophila that lack PIWI proteins shows increased DNA damage and an activated meiotic checkpoint during oogenesis. The work defined in Aim 1 of this proposal will characterize the type of DNA damage and genomic instability that occurs in PIWI deficient Drosophila at the basepair resolution using novel deep-sequencing based techniques.
In Aim 2, the mechanism used by PIWI proteins to help maintain genome stability will be determined, with a focus on how the PIWI-piRNA pathway interacts with the DNA damage checkpoint mechanism to ensure genome integrity.
Many human diseases such as cancer and neurodegenerative diseases are caused by the accumulation of DNA mutations. Understanding how cells normally prevent and repair DNA damage will help with the development of therapies to prevent or treat human diseases caused by DNA damage. The research in this proposal will examine how PIWI proteins protect against the accumulation of DNA mutations.
