Chromodomain-helicase-DNA-binding protein 1-like (ALC1) (ALC1)

Chromodomain-helicase-DNA-binding protein 1-like (CHD1L), commonly known as ALC1 (Amplified in Liver Cancer 1), is an ATP-dependent chromatin remodeling enzyme and DNA helicase belonging to the SNF2 superfamily. It plays a pivotal role in the DNA damage response by recognizing poly(ADP-ribose) (PAR) chains at sites of DNA lesions via its C-terminal macrodomain. This recognition relieves the protein's autoinhibitory state, allowing its ATPase motor to drive nucleosome sliding and chromatin relaxation, which facilitates the recruitment of repair factors for base excision repair and homologous recombination. ALC1 is frequently overexpressed in various solid tumors, including hepatocellular, breast, and colorectal cancers, where it acts as an oncogene promoting tumor progression, metastasis, and resistance to chemotherapy. Recent research has identified ALC1 as a promising therapeutic target, particularly in homologous recombination-deficient (HRD) cancers, due to its synthetic lethal relationship with BRCA1/2 mutations. Small molecule inhibitors, such as the clinical-stage allosteric inhibitor EIS-12656, work by blocking ALC1 activity and inducing the trapping of ALC1 and PARP proteins on chromatin. This mechanism enhances genomic instability and sensitizes cancer cells to PARP inhibitors and other DNA-damaging agents. Consequently, ALC1 inhibition represents a novel strategy to overcome PARP inhibitor resistance and expand the therapeutic window for treating advanced malignancies.

Other names

Amplified in liver cancer 1Amplified in liver cancer protein 1CHD1LCHDLChromo domain-containing protein 1-like

ALC1 is an ATP-dependent chromatin remodeler activated by poly(ADP-ribose) (PAR) chains synthesized by PARP1/2 at DNA damage sites. It binds PAR via its macrodomain, relieving autoinhibition and allowing its ATPase motor to slide nucleosomes, which relaxes chromatin and facilitates DNA repair. Inhibitors allosterically block this activity, leading to the trapping of ALC1 and PARP on chromatin, causing genomic instability and apoptosis, especially in HR-deficient cells.