Skirmantas Kriaucionis selected recent publications

Tomkova M, Tomek J, Kriaucionis S, Schuster-Böckler B. 2018. Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biol, 19 (1), pp. 129. | Show Abstract | Read more

BACKGROUND: DNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes. Here, we use somatic mutation signatures-each representing a mutagenic process-derived from 3056 patients spanning 19 cancer types to quantify the strand asymmetry of mutational signatures around replication origins and between early and late replicating regions. RESULTS: We observe that most of the detected mutational signatures are significantly correlated with the timing or direction of DNA replication. The properties of these associations are distinct for different signatures and shed new light on several mutagenic processes. For example, our results suggest that oxidative damage to the nucleotide pool substantially contributes to the mutational landscape of esophageal adenocarcinoma. CONCLUSIONS: Together, our results indicate an interaction between DNA replication, the associated damage repair, and most mutagenic processes.

Motnenko A, Liang C-C, Yang D, Lopez-Martinez D, Yoshikawa Y, Zhan B, Ward KE, Tian J, Haas W, Spingardi P et al. 2018. Identification of UHRF2 as a novel DNA interstrand crosslink sensor protein. PLoS Genet, 14 (10), pp. e1007643. | Show Abstract | Read more

The Fanconi Anemia (FA) pathway is important for repairing interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix. An initial and essential stage in the repair process is the detection of the ICL. Here, we report the identification of UHRF2, a paralogue of UHRF1, as an ICL sensor protein. UHRF2 is recruited to ICLs in the genome within seconds of their appearance. We show that UHRF2 cooperates with UHRF1, to ensure recruitment of FANCD2 to ICLs. A direct protein-protein interaction is formed between UHRF1 and UHRF2, and between either UHRF1 and UHRF2, and FANCD2. Importantly, we demonstrate that the essential monoubiquitination of FANCD2 is stimulated by UHRF1/UHRF2. The stimulation is mediating by a retention of FANCD2 on chromatin, allowing for its monoubiquitination by the FA core complex. Taken together, we uncover a mechanism of ICL sensing by UHRF2, leading to FANCD2 recruitment and retention at ICLs, in turn facilitating activation of FANCD2 by monoubiquitination.

Fernandez-Rozadilla C, Kartsonaki C, Woolley C, McClellan M, Whittington D, Horgan G, Leedham S, Kriaucionis S, East JE, Tomlinson I. 2018. Author Correction: Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel. Br J Cancer, 118 (12), pp. 1683. | Show Abstract | Read more

Since the publication of this paper, the authors noticed that James E. East was assigned to the incorrect affiliation. The affiliation information is provided correctly, above.

Tomkova M, McClellan M, Kriaucionis S, Schuster-Böckler B. 2018. Erratum to "DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine"[DNA Repair, 62 (2018) 1-7]. DNA Repair (Amst), 65 pp. 79. | Show Abstract | Read more

© 2018 Elsevier B.V. The publisher regrets that some symbols were incorrectly typeset. All occurrences of “≫ >” have been corrected to “≫”. The publisher would like to apologise for any inconvenience caused.

Mulvey B, Bhatti DL, Gyawali S, Lake AM, Kriaucionis S, Ford CP, Bruchas MR, Heintz N, Dougherty JD. 2018. Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus. Cell Rep, 23 (8), pp. 2225-2235. | Show Abstract | Read more

Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females-which we leverage to illustrate the behavioral and pharmacologic relevance of these findings-and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.

Fernandez-Rozadilla C, Kartsonaki C, Woolley C, McClellan M, Whittington D, Horgan G, Leedham S, Kriaucionis S, East J, Tomlinson I. 2018. Telomere length and genetics are independent colorectal tumour risk factors in an evaluation of biomarkers in normal bowel. Br J Cancer, 118 (5), pp. 727-732. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Colorectal cancer (CRC) screening might be improved by using a measure of prior risk to modulate screening intensity or the faecal immunochemical test threshold. Intermediate molecular biomarkers could aid risk prediction by capturing both known and unknown risk factors. METHODS: We sampled normal bowel mucosa from the proximal colon, distal colon and rectum of 317 individuals undergoing colonoscopy. We defined cases as having a personal history of colorectal polyp(s)/cancer, and controls as having no history of colorectal neoplasia. Molecular analyses were performed for: telomere length (TL); global methylation; and the expression of genes in molecular pathways associated with colorectal tumourigenesis. We also calculated a polygenic risk score (PRS) based on CRC susceptibility polymorphisms. RESULTS: Bowel TL was significantly longer in cases than controls, but was not associated with blood TL. PRS was significantly and independently higher in cases. Hypermethylation showed a suggestive association with case:control status. No gene or pathway was differentially expressed between cases and controls. Gene expression often varied considerably between bowel locations. CONCLUSIONS: PRS and bowel TL (but not blood TL) may be clinically-useful predictors of CRC risk. Sample collection to assess these biomarkers is feasible in clinical practice, especially where population screening uses flexible sigmoidoscopy or colonoscopy.

Tomkova M, McClellan M, Kriaucionis S, Schuster-Böckler B. 2018. DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine. DNA Repair (Amst), 62 pp. 1-7. | Citations: 2 (Web of Science Lite) | Show Abstract | Read more

Transitions of cytosine to thymine in CpG dinucleotides are the most frequent type of mutations observed in cancer. This increased mutability is commonly explained by the presence of 5-methylcytosine (5mC) and its spontaneous hydrolytic deamination into thymine. Here, we describe observations that question whether spontaneous deamination alone causes the elevated mutagenicity of 5mC. Tumours with somatic mutations in DNA mismatch-repair genes or in the proofreading domain of DNA polymerase ε (Pol ε) exhibit more 5mC to T transitions than would be expected, given the kinetics of hydrolytic deamination. This enrichment is asymmetrical around replication origins with a preference for the leading strand template, in particular in methylated cytosines flanked by guanines (GCG). Notably, GCG to GTG mutations also exhibit strand asymmetry in mismatch-repair and Pol ε wild-type tumours. Together, these findings suggest that mis-incorporation of A opposite 5mC during replication of the leading strand might be a contributing factor in the mutagenesis of methylated cytosine.

Brown DA, Di Cerbo V, Feldmann A, Ahn J, Ito S, Blackledge NP, Nakayama M, McClellan M, Dimitrova E, Turberfield AH et al. 2017. The SET1 Complex Selects Actively Transcribed Target Genes via Multivalent Interaction with CpG Island Chromatin. Cell Rep, 20 (10), pp. 2313-2327. | Citations: 5 (European Pubmed Central) | Show Abstract | Read more

Chromatin modifications and the promoter-associated epigenome are important for the regulation of gene expression. However, the mechanisms by which chromatin-modifying complexes are targeted to the appropriate gene promoters in vertebrates and how they influence gene expression have remained poorly defined. Here, using a combination of live-cell imaging and functional genomics, we discover that the vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in a form of multivalent chromatin reading that involves recognition of non-methylated DNA and histone H3 lysine 4 trimethylation (H3K4me3). CFP1 defines SET1 complex occupancy on chromatin, and its multivalent interactions are required for the SET1 complex to place H3K4me3. In the absence of CFP1, gene expression is perturbed, suggesting that normal targeting and function of the SET1 complex are central to creating an appropriately functioning vertebrate promoter-associated epigenome.

Kriaucionis S. 2017. DNA Extras SCIENTIST, 31 (9), pp. 48-53.

Bardella C, Al-Dalahmah O, Krell D, Brazauskas P, Al-Qahtani K, Tomkova M, Adam J, Serres S, Lockstone H, Freeman-Mills L et al. 2016. Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis. Cancer Cell, 30 (4), pp. 578-594. | Citations: 23 (Web of Science Lite) | Show Abstract | Read more

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Total publications on this page: 10

Total citations for publications on this page: 32