Co-functionality of AlkB and BER DNA Repair Genes in Response to Chemotherapeutic Agents
Engineering
BME 195 Senior Thesis
ALKB homologs (ALKBH) constitute a family of genes with oxoglutarate-
and iron-mediated oxidation activity that are involved in various aspects of nucleic acid
homeostasis, including repair of DNA alkylation damage. Another mechanism of DNA
repair, base excision repair (BER), resolves non-bulky lesions introduced by alkylation
as well. While ALKBH activity is error-free and typically does not require protein
partners, BER involves the generation of intermediates, requiring the coordinated action
of several enzymes. In an attempt to identify potential functional partnerships between
these two mechanisms of alkylation repair and to shed light into the roles of orphan
ALKBH genes, we analyzed basal transcription patterns for ALKBH1-8 and for a panel of
19 BER genes in 57 non-redundant NCI-60 tumor cell lines. We find a very strong
correlation between average transcriptional levels for the two sets of DNA repair genes.
Ranking of ALKBH-BER gene pairs showing the highest transcriptional correlation and
segregation by principal component analysis suggest a functional interaction for
ALKBH2, 4, and possibly 7, and another for ALKBH 1 and 3. These observations point
to a multi-layered functional collaboration between ALKBH and BER, which has a
precedent with the adaptive response to alkylation in bacteria and fits with emerging
evidence of cross-talk between DNA repair pathways. We support the biological
relevance of the most significant ALKBH-BER pairwise correlations by showing that they
are preferentially co-amplified in two different tumor types. Co-expression and co-
amplification data specifically points to a functional interaction involving ALKBH2 and 4
with PARP1, ALKBH1 and 3 with Polβ. This work expands our mechanistic
understanding of ALKBH action. It also implies that, through their functional cooperation
with BER, ALKBH genes could modulate tumor sensitivity to chemotherapy beyond the
direct repair of their canonical substrates. We intend to extend this analysis to identify
functional interactions between ALKBH and BER repair pathways in populations of adult
and embryonic stem cells as compared with lineage committed progenitor cells.
