The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss.
E2F is a family of transcription factors that regulate the expression of genes involved in a wide range of cellular processes, including cell-cycle progression, DNA replication, DNA repair, differentiation, and apoptosis. E2F1, the founding member of the family, undergoes posttranslational modifications in response to DNA damage, resulting in E2F1 stabilization. In some cases, E2F1 is important for DNA damage-induced apoptosis through the transcriptional activation of p73 and perhaps other proapoptotic target genes. However, in other contexts, E2F1 can stimulate DNA repair and promote survival in response to DNA damage. The E2F1 protein accumulates at sites of both DNA double-strand breaks and UV radiation-induced damage, indicating that E2F1 has a nontranscriptional function at sites of damage. This review summarizes recent progress made in understanding the role of E2F1 in the DNA damage response, including transcription-independent activities that facilitate DNA repair in the context of chromatin.
Metastatic cancer patients experience a severe loss of skeletal muscle
mass and function known as cachexia. Cachexia is associated with poor prognosis
and accelerated death in cancer patients, yet its underlying mechanisms remain
poorly understood. Here, we identify the metal transporter ZIP14 as a critical
mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles
from mice and patients with metastatic cancer and can be induced by
TNF-α and TGF-β cytokines.Strikingly, in vivo manipulation of Zip14 expression has
profound impact on muscle atrophy in experimental models of metastasis.We find that ZIP14-mediated zinc uptake in muscle progenitor cells
represses the expression of the key myogenic factors MyoD and
Mef2c, and blocks muscle-cell differentiation. Importantly,
ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin
heavy chain loss. These results highlight a previously unrecognized role for
altered zinc homeostasis in muscle during metastatic-cancer-induced cachexia,
and implicate ZIP14 as a therapeutic target for its treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.