The ERCC1 gene, also known as Excision Repair Cross-Complementation Group 1, is a human gene located on chromosome 19. It produces a protein that forms a complex with XPF (also known as ERCC4), creating the ERCC1-XPF enzyme complex. This complex is a component of the body’s DNA repair machinery, which helps maintain the stability of our genetic material.
ERCC1: The DNA Repair Maestro
The ERCC1-XPF complex functions in the Nucleotide Excision Repair (NER) pathway, a system designed to correct various types of DNA damage. This damage can arise from external sources, such as ultraviolet (UV) light exposure, or from internal cellular processes. The NER pathway is effective at repairing bulky lesions on the DNA strand, which can distort the DNA helix and interfere with normal cellular functions.
The ERCC1-XPF complex functions as a structure-specific nuclease, cutting DNA where a single strand meets a double strand. In the NER pathway, this complex makes an incision on the 5′ side of the damaged DNA segment. This incision allows the damaged section to be removed and replaced with new, undamaged DNA. The ERCC1 protein mediates interactions with DNA and other proteins, while XPF provides the cutting ability. Maintaining DNA integrity through pathways like NER helps prevent mutations that can lead to diseases, including cancer.
ERCC1’s Role in Cancer Treatment
ERCC1’s function in DNA repair impacts the effectiveness of certain cancer treatments, particularly those using platinum-based chemotherapy agents. Drugs like cisplatin and oxaliplatin work by creating DNA damage, forming crosslinks within and between DNA strands, which leads to cancer cell death. The ability of cancer cells to repair this damage can determine their sensitivity or resistance to these drugs.
When ERCC1 levels are high in cancer cells, their DNA repair machinery is more active, allowing them to efficiently repair damage from platinum-based chemotherapy. This increased repair capacity can lead to drug resistance, making chemotherapy less effective. Conversely, cancer cells with low ERCC1 levels have a reduced ability to repair DNA damage, making them more sensitive to these drugs. Cell lines deficient in the ERCC1-XPF complex are more sensitive to cisplatin, demonstrating the link between ERCC1 activity and chemotherapy response.
ERCC1 as a Predictive Biomarker
Given its influence on chemotherapy effectiveness, ERCC1 has been investigated as a predictive biomarker in cancer treatment. A biomarker is a measurable indicator that can help predict how a patient might respond to a specific therapy. Measuring ERCC1 levels in a patient’s tumor tissue, often through techniques like immunohistochemistry or by analyzing messenger RNA (mRNA) expression, aims to guide treatment decisions.
For instance, studies in non-small cell lung cancer indicate that patients with low ERCC1 expression tend to have a longer median survival when treated with platinum-based chemotherapy compared to those with high ERCC1 expression. This suggests that identifying patients with lower ERCC1 levels could help tailor treatments, leading to more personalized medicine. While ERCC1 is a promising biomarker, ongoing research refines methodologies and addresses complexities in its clinical application, including the performance of antibodies used for testing.