Trichothiodystrophy update on the sulfur-deficient brittle hair syndromes – journal of the american academy of dermatology significado de anoxia

Fig. 4

Model of the global genomic repair (GGR, left part) and transcription-coupled repair (TCR, right part) of UV-induced DNA lesions. The complex XP-C/HR23B is the first factor in GGR only to bind DNA lesions and to attract XPA, RPA (ssdna binding protein) and then TFIIH. The XPE protein seems to facilitate the identification of lesions, which are poorly recognized by the XPC/H23R complex (such as the CPD). Demarcation of the lesions is carried out by the two helicase activities (XPB and XPD) of TFIIH followed by sequential cleavage by the two structure-specific nucleases XPG (on 3′ side) and ERCC1-XPF (on 5′ side).


After removal of an oligonucleotide (27-30 nucleotides long) containing the lesion, DNA synthesis occurs using either polymerase δ or ϵ in presence of PCNA and RF-C complexes as processivity factors.Significado de anoxia the final NER step is ligation of the newly synthesized DNA patch to parental DNA probably by DNA ligase I. On damaged templates, RNA polymerase II is blocked by bulky lesions inducing a signal for TCR (right part). The proteins CSA, CSB, and possibly XPG and TFIIH displace the stalled RNA pol II from the lesion, which becomes accessible for further repair in the same way as for GGR.

Trichothiodystrophy (TTD) refers to a heterogeneous group of autosomal recessive disorders that share the distinctive features of short, brittle hair and an abnormally low sulfur content. Within the spectrum of the TTD syndromes are numerous interrelated neuroectodermal disorders. The TTD syndromes show defective synthesis of high-sulfur matrix proteins.Significado de anoxia abnormalities in excision repair of ultraviolet (UV)-damaged DNA are recognized in about half of the patients. Three distinct autosomal recessive syndromes are associated with nucleotide excision repair (NER) defects: the photosensitive form of TTD, xeroderma pigmentosum, and cockayne syndrome. The unifying feature of these conditions is exaggerated sensitivity to sunlight and UV radiation. In contrast to patients with xeroderma pigmentosum, no increase of skin cancers in patients with TTD has been observed. Genetically, 3 complementation groups have been characterized among photosensitive patients with TTD. Most patients exhibit mutations on the two alleles of the XPD gene. Rarely, mutated XPB gene or an unidentified TTD-A gene may result in TTD.Significado de anoxia in UV-sensitive TTD, the TFIIH transcription factor containing XPB and XPD helicase activities necessary for both transcription initiation and DNA repair is damaged. Beyond deficiency in the NER pathway, it is hypothesized that basal transcription may be altered leading to decreased transcription of specific genes. Depressed RNA synthesis may account for some clinical features, such as growth retardation, neurologic abnormalities, and brittle hair and nails. Therefore the attenuated expression of some proteins in differentiated cells is most likely explained by a mechanism distinct from DNA repair deficiency. The first transgenic mouse models for NER deficiencies have been generated. The TTD mouse as well as related cell models will provide important tools to understand the complex relationships between defects in DNA repair, low-sulfur hair shaft disorders, and the genotype-phenotype correlates for this constellation of inherited disorders, including the lack of predisposition to cancer in patients with TTD. (J am acad dermatol 2001;44:891-920.) learning objective: at the completion of this learning activity, participants will have a current understanding of the expanded and further defined clinical spectrum of the TTD syndromes.Significado de anoxia participants will have gained new insight into the genetic and molecular characteristics and causes for the low-sulfur hair disorders.