The variant histone H2AX is phosphorylated in response to UV irradiation of primary human fibroblasts in a complex fashion that is radically different from that commonly reported after DNA double-strand breaks. H2AX phosphorylation after exposure to ionizing radiation produces foci, which are detectable by immunofluorescence microscopy and have been adopted as clear and consistent quantitative markers for DNA double-strand breaks. Here we show that in contrast to ionizing radiation, UV irradiation mainly induces H2AX phosphorylation as a diffuse, even, pannuclear staining. UV induced pan-nuclear phosphorylation of H2AX is present in all phases of the cell cycle and is highest in S phase. H2AX phosphorylation in G1 cells depends on nucleotide excision repair factors that may expose the S-139 site to kinase activity, is not due to DNA double-strand breaks, and plays a larger role in UV-induced signal transduction than previously realized.ultraviolet light ͉ xeroderma pigmentosum ͉ chromatin structure ͉ Wortmannin ͉ human fibroblasts H 2AX phosphorylation plays a major role in nuclear events during meiosis and DNA double-strand breaks (DSBs). DSBs cause phosphorylation of histone H2AX on large areas of chromatin flanking the breaks (1). Phosphorylation, coupled with the acetylation-dependent condensation of chromatin, permits microscopic visualization of discrete nuclear foci (2). Phosphorylated H2AX (␥H2AX) foci formation is a powerful tool used to study DSB formation and repair after genomic damage, chromosome dynamics, and signaling mechanisms (3-7). Analysis of knockout mice and cell lines implicate H2AX phosphorylation in genomic stability, tumor suppression, and spermatogenesis (8, 9).Although H2AX phosphorylation in response to ionizing radiation and other radiomimetic agents garners a great deal of attention, its role in the UV-induced DNA damage response is not well characterized. Reports have limited ␥H2AX formation to S phase after exposure to UV-B (10, 11). We have reported previously coincidence of ␥H2AX, MRE11, and PCNA in foci that represent replication fork breakage in the S phase of SV40-transformed cells (12,13). In contrast, a recent report finds that ␥H2AX is present in HeLa and HL60 cells at 1 h after UV-B irradiation in all phases of the cell cycle (14). These studies speculate that H2AX phosphorylation after UV irradiation is induced only by processing of UV-induced lesions into DNA DSBs, but we report a more complex response.Historically, direct DNA breakage from UV-C has been undetectable in mammalian cells (15). Calculation of the maximum frequency of DNA breaks during excision repair after UV light, from these experiments, yields an estimate of 3,000-4,000 single strand breaks per diploid cell associated with nucleotide excision repair (NER) at a maximum rate within 1 h of 10-20 J͞m 2 with a separation of Ͼ10 9 Da (4 ϫ 10 6 nt) between excision sites (16-18). The number of photoproducts per cell under these conditions is Ϸ2 ϫ 10 6 , and repair operates on only Ϸ0.1% of the initial photopr...

Cockayne syndrome (CS) is a rare degenerative disorder with a common set of symptoms but a very wide variation in phenotype. The variation is sufficiently wide that CS patients have traditionally been described in three different severity groups. Unfortunately, there is no single source for information about the different severity groups. This problem can complicate not only diagnosis, but accurate prognosis as well. The goal of this study was to describe the phenotypic variation in CS as completely as possible. This article provides extensive descriptions of traits common to each group and their degree of severity in each group. Forty-five people with CS were surveyed and information from the published literature was used to increase the sample sizes for calculations. This study provides new information, including statistical data for each of the three severity groups (mean age at death, average head circumference, and average length or stature). The study includes cerebro-oculo-facial syndrome (COFS) as a severe form of CS, based on results of recently published genetic studies performed by other authors. This study proposes revised names for CS severity groups: severe, moderate, and mild. The groups were formerly called Type II/early onset CS, Type I/classical CS, and Type III/atypical/mild/late-onset CS, respectively. A fourth newly documented group, UV sensitivity only/adult onset, is also described. Average ages of death were calculated as 5.0 years (severe), 16.1 years (moderate), and 30.3 years (mild).

Xeroderma pigmentosum-Cockayne syndrome complex is a very rare multisystem degenerative disorder (Orpha: 220295; OMIM: 278730, 278760, 278780, 610651). Published information on XP-CS is mostly scattered throughout the literature. We compiled statistics related to symptom prevalence in XP-CS and have written a clinical description of the syndrome. We also drew on clinical practices used in XP and in Cockayne syndrome without XP to aid management of XP-CS.Extensive searches of the literature identified 43 XP-CS patients. The diagnosis had been confirmed with molecular or biochemical methods in 42 of them. Clinical features of each patient were summarized in spreadsheets and summary statistics were generated from this data. XP patients are classified into complementation groups according to the gene that is mutated. There are four groups in XP-CS, and classification was available for 42 patients. Twenty-one were in the XP-G complementation group, 13 in XP-D, 5 in XP-B, and 3 in XP-F. Overall, the clinical features of XP-CS are very similar to those of CS without XP, with the exception of skin cancers in XP-CS. However, one intriguing finding was that cancer incidence was lower in XP-CS compared to XP alone or XP-neurological disorder. The cancer rate in XP-CS was higher than in CS without XP, an unsurprising finding. There is preliminary evidence for the existence of severity groups in XP-CS, as is the case in CS.Although health problems in XP-CS vary both in severity and in when they the first occur, there was overall homogeneity between all complementation groups and putative severity groups. Severely affected patients met fewer milestones and died at younger ages compared to more mildly affected patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0616-2) contains supplementary material, which is available to authorized users.

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