BCLAF1 is a protein encoded by the BCLAF1 gene. It functions as a transcriptional repressor, influencing gene expression. BCLAF1 is a multi-functional protein involved in processes, maintaining cellular balance and responding to stress.
Primary Cellular Functions of BCLAF1
BCLAF1 plays a diverse role in healthy cells, contributing to cellular integrity and cell fate. Its functions include regulating programmed cell death, assisting in DNA repair, and influencing gene expression and RNA splicing. In the nucleus, BCLAF1 interacts with molecular components.
Apoptosis
BCLAF1 is involved in apoptosis, a cell self-destruction process removing unwanted or damaged cells. It promotes apoptosis by activating genes like TP53 and BAX, while inhibiting MDM2. However, BCLAF1 also contributes to anti-apoptotic pathways, protecting cells from death signals like those from TNF, by upregulating proteins such as c-FLIP. This dual capacity highlights its complex role in cell survival.
DNA Damage Response
BCLAF1 helps manage the cell’s DNA Damage Response (DDR). It partners with BACH1, a DDR factor, and is recruited to DNA damage sites to facilitate repair and maintain genomic stability. BCLAF1 deficiency can make cells more susceptible to DNA-damaging agents, leading to impaired DNA repair. It participates in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways.
Gene Expression and RNA Splicing
BCLAF1 influences gene expression and pre-mRNA splicing. It is a component of interchromatin granular clusters, which store pre-mRNA splicing factors. BCLAF1 collaborates with RNA processing factors like THRAP3 to regulate selective splicing and export of messenger RNA (mRNA) transcripts, including those encoding DDR proteins like ATM kinase. This ensures genetic instructions are prepared for protein production.
Role in Cancer Development
BCLAF1’s dysregulation can impact cancer development. It exhibits a context-dependent role, acting as either a tumor suppressor or a promoter of cancer progression, depending on the cancer type and cellular environment.
Tumor Suppressor
In some cancers, BCLAF1 functions as a tumor suppressor by promoting cell death. For instance, in colon adenocarcinoma and bladder cancer, BCLAF1 can induce apoptosis by activating TP53 and BAX, while inhibiting MDM2. In lung cancer, BCLAF1 promotes apoptosis by repressing p21, a cell cycle inhibitor. In multiple myeloma, BCLAF1 induces autophagic cell death; however, caspase-10 can cleave BCLAF1, inhibiting autophagy and promoting myeloma cell survival.
Oncogene
In contrast, BCLAF1 can act as an oncogene in other cancer types. In hepatocellular carcinoma (HCC), elevated BCLAF1 levels contribute to tumor proliferation and angiogenesis. This occurs partly by regulating HIF-1α transcription and stabilizing c-Myc mRNA, which support tumor growth. BCLAF1 also stabilizes PD-L1, a protein that helps cancer cells evade the immune system, by interfering with its degradation, promoting immune escape in HCC.
Expression Levels and Outcomes
BCLAF1’s expression levels are associated with patient outcomes in specific cancers. In colorectal cancer, high BCLAF1 mRNA expression links to a favorable overall survival, suggesting a tumor-suppressive role. Conversely, in breast cancer, high BCLAF1 mRNA expression is linked to a poor overall survival, indicating a cancer-promoting function. Deletions of the BCLAF1 gene have been identified in esophageal squamous cell carcinoma, where its knockdown leads to reduced expression of pro-apoptotic and DNA repair genes, contributing to cellular transformation.
Interaction with Viruses
Viruses often manipulate host cell machinery to replicate, and BCLAF1 is a target for viral strategies. Viruses can hijack or counteract BCLAF1’s functions to prevent infected cells from undergoing programmed cell death, allowing the virus to multiply.
Human Cytomegalovirus (HCMV)
Human cytomegalovirus (HCMV) employs mechanisms to neutralize BCLAF1, a restriction factor against the virus. Following infection, HCMV viral proteins pp71 and UL35 direct BCLAF1’s proteasomal degradation. Later, HCMV suppresses BCLAF1 levels using a virus-encoded microRNA, miR-UL112-1. These attacks are necessary for efficient viral gene expression and replication.
Alphaherpesviruses
Alphaherpesviruses, including Pseudorabies virus (PRV) and Herpes Simplex Virus type 1 (HSV-1), target BCLAF1. These viruses degrade BCLAF1 through their viral protein US3. BCLAF1 plays a role in the type I interferon response, a host antiviral defense pathway. By degrading BCLAF1, these viruses impair the host’s ability to mount an effective antiviral response.
Human Immunodeficiency Virus type 1 (HIV-1)
The human immunodeficiency virus type 1 (HIV-1) also influences BCLAF1. The HIV-1 Tat protein can delay Fas-mediated apoptosis in infected CD4+ T lymphocytes. This delay is partly attributed to Tat’s ability to promote BCLAF1 overexpression, which helps stabilize the mitochondrial membrane and prevent cell death. This mechanism contributes to HIV-1’s persistent replication within infected T cells.
Therapeutic and Research Directions
Understanding BCLAF1’s varied roles in cellular processes and disease has opened avenues for new research and potential therapeutic strategies. Researchers are exploring its utility as a prognostic biomarker to predict disease outcomes or treatment responses in cancer.
BCLAF1 expression also serves as a prognostic indicator in other cancers. In renal cell carcinoma, higher BCLAF1 expression correlates with a better patient prognosis. Conversely, in hepatocellular carcinoma (HCC), elevated BCLAF1 expression is associated with a worse prognosis and may predict resistance to certain treatments. These findings suggest that monitoring BCLAF1 levels could inform clinical decisions.
Future therapeutic approaches might involve targeting BCLAF1 or its associated molecular pathways. For instance, in HCC, strategies aimed at the BCLAF1-HIF-1α pathway or disrupting BCLAF1’s ability to stabilize PD-L1 could enhance anti-tumor immunity and improve responses to checkpoint therapies. Tumors with mutations in RNA processing factors like THRAP3 and BCLAF1 might also be sensitive to DNA-damaging chemotherapy. A challenge is developing therapies that selectively inhibit BCLAF1’s cancer-promoting activities without disrupting its beneficial functions in healthy cells.