Thesis

Investigating the Role of HDXX as a Novel DNA Damage Response Protein in Colorectal Cancer

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Colorectal cancer (CRC) ranks third in cancer incidence and cancer-related mortalities worldwide. The
transformation of normal colon and rectal cells to malignant adenocarcinomas due to unrepaired DNA
damage which leads to oncogenic mutations. These mutations also increase the frequency of DNA
damage, leading to endogenous replication stress (RS). This introduces an opportunity to induce
synthetic lethality in CRC cells by exacerbating RS to intolerable. Notably, the SQ motif of a novel
protein, HDXX has been shown to be phosphorylated following ionizing radiation, which pinpoints its
role downstream of ATR and ATM kinases which are activated in response to RS and double-stranded
breaks (DSBs), respectively. Thus, this thesis project aims to investigate the role of HDXX in the
ATR/CHK1 pathway which constitutes the RS response (RSR) through the generation of stable HDXX
knockdown HCT116 cells, western blot analysis, as well as gene ontology (GO) and gene set enrichment
analysis (GSEA). HDXX was found to not play a role in the ATR/CHK1 pathway, with knockdown leading
to a statistically insignificant effect on pRPA and pCHK1 protein levels following HU treatment. As SQ
motif phosphorylation is specific to ATR and ATM kinases, HDXX appears to instead function in double-
strand break repair downstream of ATM. GO and GSEA analysis supports this, by suggesting the
potential involvement of HDXX in the homologous recombination pathway. As the ATM pathway is
currently understudied, it would be important to investigate the potential role of HDXX in this pathway
in future studies through the use of corresponding assays.

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Availability

Detail Information

Series Title

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Call Number

BM 24-024

Publisher

i3L, Jakarta : i3L Press., 2024

Collation

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Language

English

ISBN/ISSN

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Classification

NONE

Content Type

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Media Type

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Carrier Type

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Edition

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Subject(s)

colorectal cancer
synthetic
DNA damage response
ATR/CHK1 pathway
Replication stress

Specific Detail Info

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Statement of Responsibility

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