In the realm of genomic stability, DNA double-strand breaks (DSBs) represent one of the most severe forms of DNA damage. Cells have evolved several mechanisms to repair these breaks, with
Microhomology-mediated end joining (MMEJ) being one of the less precise methods. This pathway has gained attention in cancer research due to its implications in genomic instability and tumorigenesis.
What is Microhomology-mediated End Joining?
MMEJ is an error-prone DNA repair pathway that utilizes small regions of homology, typically 5-25 base pairs, to align broken DNA ends. Unlike the more accurate
homologous recombination (HR) and
non-homologous end joining (NHEJ), MMEJ often leads to deletions or insertions at the repair site. This occurs because the pathway involves the processing of DNA ends to reveal microhomologies, leading to the excision of non-homologous sequences.
How is MMEJ Linked to Cancer?
MMEJ's error-prone nature can contribute to
genomic instability, a hallmark of cancer. The frequent deletions and insertions associated with MMEJ can lead to mutations or chromosomal rearrangements, which may activate oncogenes or inactivate tumor suppressor genes. Studies have shown that MMEJ is upregulated in certain cancers, which suggests that tumor cells might exploit this pathway to survive under genotoxic stress, such as chemotherapy or radiation.
What Regulates MMEJ in Cancer Cells?
The regulation of MMEJ involves several proteins distinct from those in the NHEJ and HR pathways. Key proteins include
PARP1, which senses DNA damage, and
FEN1, which processes DNA flaps. Additionally,
Polθ is a crucial enzyme in MMEJ, facilitating the extension of DNA ends using microhomology. Overexpression of Polθ has been observed in various cancers, correlating with poor prognosis, suggesting it could serve as a potential therapeutic target.
Can Targeting MMEJ Pathway Be a Therapeutic Strategy?
Given MMEJ's role in promoting mutations and resistance to therapy, targeting this pathway may offer novel cancer treatments. Inhibitors of
Polθ are being investigated to enhance the efficacy of existing therapies by increasing cancer cell sensitivity to DNA-damaging agents. Additionally, combining MMEJ inhibition with other DNA repair inhibitors, like
PARP inhibitors, could provide a synthetic lethality approach, selectively killing cancer cells deficient in HR while sparing normal cells.
What Are the Challenges in Targeting MMEJ?
While the therapeutic potential is promising, several challenges exist in targeting MMEJ. The redundancy and overlap between DNA repair pathways can lead to compensatory mechanisms that reduce the efficacy of MMEJ inhibitors. Furthermore, the specificity of such inhibitors is crucial to minimize off-target effects and toxicity in normal cells. Developing selective inhibitors that specifically target cancer cells with heightened MMEJ activity remains a significant hurdle.
How is MMEJ Detected in Tumors?
Detecting MMEJ activity in tumors involves analyzing specific mutation signatures or structural variations characteristic of this repair pathway. Next-generation sequencing (NGS) technologies have facilitated the identification of these patterns, allowing researchers to correlate MMEJ activity with clinical outcomes. Moreover, the presence of microhomology-associated deletions in tumor DNA can serve as biomarkers for the reliance on MMEJ, aiding in the stratification of patients for targeted therapies.
Conclusion
Microhomology-mediated end joining plays a complex role in cancer development and progression by contributing to genomic instability. Understanding the intricacies of this pathway offers opportunities for novel therapeutic interventions. However, the challenges in selectively targeting MMEJ without affecting normal cellular functions highlight the need for further research. As our knowledge of DNA repair mechanisms deepens, MMEJ may become a pivotal focus in precision oncology, offering hope for more effective cancer treatments.
