BRCA1

Autophagy: Pro or Anti-tumorigenic? And the role of epigenetics in this debate

By Christina Towers, PhD

Further unraveling the role of gamma H2AX in DNA damage response

Our genome experiences a moderate amount of DNA damage in our cells on a daily basis.  This DNA damage can be in response to external environmental factors, or be a result of our internal metabolic processes going awry.  While normal rates of DNA damage are not an immense threat to our cell processes, DNA damage in critical genes can lead to a variety of disease, including cancer and tumor formation.   After induction of DNA damage (for example, in the form of double strand breaks), phosphorylation and recruitment of the H2AX protein occurs.  This phosphorylation produces gamma H2AX

The recent relationship of BRCA1 and 53BP1

The p53-binding protein 1 (53BP1) is a DNA damage response factor, which is recruited to nuclear structures at the site of DNA damage.  DNA double-strand breaks (DSBs) are mutations that are detrimental to cell viability and genome stability, and must be repaired either through homologous recombination (HR) or non-homologous end joining (NHEJ). 53BP1 specifically promotes both NHEJ as well as the inhibition of HR repair, yet the decision making on a molecular level between these two routes not clearly understood.

ATM - detecting and responding to DNA damage

Ataxia telangiectasia mutated (ATM) is essential for the maintenance of genomic stability. ATM is a 370 kDa serine-threonine kinase that is constitutively expressed in various tissues. Although primarily nuclear, ATM is also found at lower levels associated with cytoplasmic vesicles. As a PI 3-kinase family member, ATM is able to phosphorylate a wide variety of substrates including proteins involved in sensing and repairing DNA damage such as p53 and Brca1 (2). Normally ATM is found as an inactive homodimer.

FANCD2 (Fanconi anemia subunit D2 protein)

Fanconi anemia (FANC) is a rare, autosomal-recessive genetic disorder that is a heterogeneous cancer susceptibility condition that manifests with a wide range of symptoms such as congenital malformations, deteriorating bone marrow failure, DNA-damage hypersensitivity, genomic instability, and increased cancer incidence. FANCD2 is a component within the protein complex that is involved in a cell's resistance to DNA cross-linking and subsequent DNA synthesis arrest that is stimulated by the insult of ionizing radiation (IR).

53BP1 - a marker for DNA Double Strand Break

53BP1 (p53 binding protein 1) was originally thought to be an enhancer for p53 transcriptional, but later studies have demonstrated that it is actually a substrate for ataxia telangiectasia mutated (ATM). 53BP1 is a classic late DNA damage response (DDR) marker that is present during the cell cycle phases of telophase and cytokinesis (within mitotic mammalian cells).

FANCD2: A big component of the DNA repair crew

The genetic disorder known as Fanconi anemia (FANC) is a heterogeneous, autosomal-recessive cancer susceptibility condition characterized by a wide array of symptoms. These include congenital malformations, progressive bone marrow failure, DNA-damage hypersensitivity, and genome instability. The protein FANCD2 is a subunit of the protein complex involved in cellular resistance to DNA cross-linking and DNA synthesis arrest triggered by ionizing radiation (IR).

BRCA1 - A Critical Tumor Suppressor Gene in Women

Breast cancer 1, early onset (BRCA1) is a well-known tumor suppressor gene that was originally discovered due to its link with early-onset breast and ovarian cancer in women. The BRCA1 protein contains the following domains: RING finger, RAD51-interaction, and BRCT (BRCA1 C-terminus). The N-terminus RING domain enables binding to several proteins - including BARD1 (BRCA1-associated RING domain protein) - allowing the formation of heterodimers. The RING finger is important for tumor suppressor activity. The RAD51-interaction domain is involved in DNA double-stranded break (DSB) repair.

53BP1 - DNA damage is no fun

The 53BP1 (p53 binding protein 1) was initially believed to be a p53 transcriptional enhancing partner, but it has now been established as an ataxia telangiectasia mutated (ATM) substrate. As a late DNA damage response (DDR) marker, 53BP1 appears during the telophase and cytokinesis phase of mitotic mammalian cells1.

Breast Cancer Infographic

Breast cancer is caused by malignant cells developing in breast tissue. It is the most commonly diagnosed cancer in women, but advancements in treatment options have seen the death rate decline since the 1990s. Common warning signs of breast cancer include lumps, changes in breast size or shape, discoloration, dimpling of the skin, new concentrated pain in the breast, and rash on the nipple.  Yearly mammograms and self-exams are an important part of early detection of breast cancer.

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