![]() These breaks would normally be repaired through the same NHEJ mechanism as radiation-induced damage. Īgents Responsible for Double Stranded DNA BreaksĪlthough defects in NHEJ are classically considered to produce “radiosensitive” forms of SCID, in fact, a wide variety of agents other than ionizing radiation produce dsDNA breaks via reactive oxygen species. Another factor, known as Cernunnos-XLF, accumulates at the site of dsDNA breaks and appears to stimulate the DNA Ligase IV: XRCC4 complex. Finally, the two ends of DNA are ligated together, a task carried out by a complex of two proteins: DNA Ligase IV and X-ray cross-complementation group 4 protein (XRCC4). This complex performs two functions via it’s nuclease activity: first, it opens the DNA hairpins created by the RAG complex and second, it acts to trim the ends to variable extents, thereby contributing to functional diversity. Ku then recruits a complex made up of two proteins: Artemis (also known as DNA cross-link repair enzyme 1C, or DCLRE1C) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). After a dsDNA break is created, the first protein that binds to the ends of the dsDNA breaks is a heterodimer known as Ku 80/86. The NHEJ pathway is especially critical in the repair of the dsDNA breaks created by the RAG process during the V(D)J recombination in T- and B- lymphocytes ( Figure 2). Defects in genes that produce components of the homologous recombination pathway result in diseases such as Ataxia Telangiectasia, Seckel Syndrome, Nijimegan Breakage Syndrome, and Fanconi Anemia, which are characterized by physical abnormalities with either immunodeficiency and/or predisposition to cancer development. Įukaryotic cells possess two mechanisms by which dsDNA breaks are repaired: homologous recombination (HR) and non-homologous end joining (NHEJ). However, once the dsDNA breaks are created by the RAG complex, proper repair must take place in order to avoid a differentiation arrest, which in B cells occurs at the transition from cytoplasmic Igμ negative to Igμ positive pre-B cells, and in T cells occurs at the transition from pro-T to double negative pro-T cells. Defects in RAG also produce a T-B- form of SCID, but without radiosensitivity. The first step in V(D)J recombination involves creation of double-stranded DNA (dsDNA) breaks and subsequent hairpin formation by an enzymatic complex produced by the Recombination Activating genes (RAG) 1 and 2 ( Figure 1). A variety of genetic mutations have now been linked to the T-B- phenotype, most of which result in defects in the protein machinery required for the V(D)J recombination events critical for producing the diverse repertoire of the T- and B-cell immune system. The T-B- phenotype accounts for approximately 30% of SCID patients and is associated with worse outcomes following hematopoietic cell transplantation (HCT) in most, but not all studies. Severe Combined Immunodeficiency Disease (SCID) has classically been divided into those patients with residual B cells (T-B+ phenotype) and those whose defects produce an absence of both T cells and B cells (T-B- phenotype). Significantly more research needs to be done in order to determine the long-term outcomes of radiosensitive SCID patients following HCT, as well as to discover novel non-toxic approaches to HCT that might benefit those with intrinsic radio- and chemo-sensitivity, as well as potentially all patients undergoing an HCT. Because of their sensitivity to certain forms of chemotherapy, the approach to donor selection and type of conditioning regimen utilized for a radiosensitive SCID patient requires careful consideration. ![]() Known etiologies of radiosensitive SCID include deficiencies of Artemis, DNA Ligase IV, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and Cernunnos-XLF, all of which have been treated with HCT. Patients with the radiosensitive form of SCID may also have increased short- and long-term sensitivity to the alkylator-based chemotherapy regimens traditionally utilized for conditioning prior to allogeneic hematopoietic cell transplantation (HCT). ![]() Inherited defects in components of the non-homologous end joining DNA repair mechanism produce a T-B-NK+ severe combined immunodeficiency disease (SCID) characterized by heightened sensitivity to ionizing radiation.
0 Comments
Leave a Reply. |