Multifaceted control of DNA repair pathways by the hypoxic tumor microenvironment

Abstract

Hypoxia, as a pervasive feature in the microenvironment of solid tumors, plays a significant role in cancer progression, metastasis, and ultimately clinical outcome. One key cellular consequence of hypoxic stress is the regulation of DNA repair pathways, which contributes to the genomic instability and mutator phenotype observed in human cancers. Tumor hypoxia can vary in severity and duration, ranging from acute fluctuating hypoxia arising from temporary blockages in the immature microvasculature, to chronic moderate hypoxia due to sparse vasculature, to complete anoxia at distances more than 150 μM from the nearest blood vessel. Paralleling the intra-tumor heterogeneity of hypoxia, the effects of hypoxia on DNA repair occur through diverse mechanisms. Acutely, hypoxia activates DNA damage signaling pathways, primarily via post-translational modifications. On a longer timescale, hypoxia leads to transcriptional and/or translational downregulation of most DNA repair pathways including DNA double-strand break repair, mismatch repair, and nucleotide excision repair. Furthermore, extended hypoxia can lead to long-term persistent silencing of certain DNA repair genes, including BRCA1 and MLH1, revealing a mechanism by which tumor suppressor genes can be inactivated. The discoveries of the hypoxic modulation of DNA repair pathways have highlighted many potential ways to target susceptibilities of hypoxic cancer cells. In this review, we will discuss the multifaceted hypoxic control of DNA repair at the transcriptional, post-transcriptional, and epigenetic levels, and we will offer perspective on the future of its clinical implications.

Keywords: DNA damage response; DNA repair; Gene regulation; Gene silencing; Genetic instability; Hypoxia; Post-translational modifications; Replication stress; Tumor microenvironment.

Figure 1. DNA damage response signaling pathways activated by acute hypoxia and mediated by post-translational modifications

ATR, activated by replication stress, and ATM, activated by the combination of replication stress and chromatin alterations, signal to downstream transducer and effector proteins. This signaling cascade leads to replication fork stabilization, chromatin relaxation, regulation of DNA repair pathway choice, cell cycle arrest, and potentially apoptosis. Several DNA damage response factors also contribute to stabilization and activation of HIF-1α.

Figure 2. Mechanisms involved in hypoxia-induced regulation of DNA repair gene expression

The HR, MMR, NER, BER, NHEJ, and TLS DNA repair pathways undergo hypoxic regulation via transcriptional, translational, or epigenetic modulation of multiple DNA repair proteins. Transcription factors, microRNAs, and chromatin modifying enzymes implicated in regulating these proteins are indicated in parentheses.

Figure 3. General time course over which hypoxia induces different regulatory mechanisms controlling DNA repair and potential associated clinical implications

Acute severe hypoxia activates PTM-mediated DNA damage signaling pathways that can be abrogated via inhibition of DNA damage signaling kinases. More chronic hypoxia leads to translational and transcriptional downregulation of DNA repair capacity, which generates cellular sensitivity to certain DNA damaging agents, radiotherapy, and PARP inhibitors. Prolonged moderate hypoxia induces stable silencing of specific DNA repair genes, which may be candidate tumor suppressor genes for reactivation. Drugs targeting hypoxia-induced DNA repair alterations may benefit from combination with agents that interact with hypoxia, such as angiogenesis inhibitors or hypoxia-activated prodrugs.