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Title page for ETD etd-07022018-103550

Type of Document Dissertation
Author Andrews, Alex Michael
URN etd-07022018-103550
Title SAN1 - a novel nuclease involved in interstrand cross-link repair
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Matthew Tyska Committee Chair
David Cortez Committee Member
Ian Macara Committee Member
James Dewar Committee Member
Jim Goldenring Committee Member
  • ICL
  • interstrand cross-link repair
  • DNA damage
  • DNA repair
Date of Defense 2018-06-21
Availability unrestricted
The DNA damage response consists of complex signaling pathways that act to recognize and remove various types of genomic insults. One particularly dangerous type of lesion is an interstrand cross-link (ICL). ICLs are extremely dangerous for a cell as they block fundamental biological processes such as replication and transcription. Most commonly ICLs occur through the introduction of chemotherapeutic compounds including Cisplatin and Mitomycin C, two agents used in the treatment of breast and ovarian cancers. Defects in ICL repair can leave to severe consequences including genomic instability and cancer. The canonical pathway for the repair of these lesions is known as the Fanconi anemia pathway, and functions during DNA replication. However, other mechanisms exist in cells to respond and remove ICLs. Here we identify a previously uncharacterized nuclease as an important protein involved in the repair of ICLs, which we have named SAN1. SAN1 possesses 5’ to 3’ nuclease activity, and functions outside of the canonical Fanconi anemia pathway. Loss of SAN1 leads to ICL sensitivity and increased DNA damage in response of cross-linking agents. Moreover, we demonstrate that SAN1 functions with the RNA/DNA helicase Senataxin to participate in the cellular response to ICLs.
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