FANCD2 and DNA damage repair

Fri, 07/22/2016 - 13:30

Fanconi anemia (FA) is a genetically inherited disorder that yields cytogenetic instability, hypersensitivity to DNA crosslinking compounds and defective DNA repair. A variety of genes have been identified within the FA pathway that are referred to as the Fanconi anemia complementation group.  One member of this group, FANCD2, is monoubiquitinated in response to DNA damage.  At this point, FANCD2 specifically localizes to the nucleus to represent the site of DNA repair, often times to the DNA replication fork. In addition to monoubiquitination, FANCD2 can also be phosphorylated by the cell checkpoint kinases ATM and ATR.  Using a FANCD2 antibody to further elucidate the role of FANCD2 the DNA damage pathway is a popular approach to understanding DNA repair in a variety of experimental models.  

FANCD2 antibody

FANCD2 Antibody [NB100-182] - Analysis using the Biotin conjugate of NB100-182. FancD2 colocalizes in vivo with another protein in SiHa cells after cell exposure to IR. Proliferating SiHa cells were exposed to 10 Gy of IR and double -color immunofluorescence staining was performed after 8 h. Images were captured in a Kodak digital image system on a Leica fluorescence microscope.

The first group in discussion is Zhou et al, who used a FANCD2 antibody in their research on chronic kidney disease, specifically karyomegalic interstitial nephritis (KIN).  While their studies focused primarily on FAN1 – the Fanconi anemia-associated nuclease 1 is recruited to sites of DNA damage by interacting with a monoubiquitinated FANCI-FANCD2 complex.  First, a FAN1 antibody and a FANCD2 antibody were used in immunohistochemistry to establish the expression levels of both FAN1 and FANCD2 in tissue and organ samples.  This group found that FAN1 was present in an abundance of organs, where FANCD2 was present in nearly 6 types lymphatic or bone marrow sources, as well as skin and testis.  Once this was determined, they went on to find that in the absence of FAN1 there was an increase in DNA damage response (DDR) and apoptosis. 

In a recent Nature article, Minocherhomji et al used a FANCD2 antibody as DNA damage response induction marker in their studies to prove that replication stress is responsible for DNA repair synthesis during mitosis.  A predicted driver of tumorogenesis has been presented where oncogene induced DNA replication stress is responsible.  Specifically, cells that enter into mitosis activate the presence of MUS81 to attend to common fragile sites on the chromosome in order to repair.  However, their research suggests that this attempt at rescuing the common fragile sites actually turns on DNA replication, which in turn causes chromosomal instability (as noted with the use of a FANCD2 antibody).

Overall, the understanding DNA repair is of high importance given its involvement in several biological processes.  Aside from day to day biological processes, pin pointing the mechanisms of DNA repair through the FA pathway, or even in other models, has promise to determine sensitivity of cancer cells to chemotherapeutics.  The latest finding in FANCD2 research is the proposition that FANCI is required to activate the FANCD2 pathway, and may need deubiquitination and dephosphorylation for this to occur. 

  1. PMID: 26430909
  2. PMID: 26633632
  3. PMID: 22772369

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