Abdelghani Mazouzi

Netherlands Cancer Institute · Brummelkamp, T. Lab

DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no cura...

The cellular response to replication stress requires the DNA-damage-responsive kinase ATM and its cofactor ATMIN; however, the roles of this signaling pathway following replication stress are unclear. To identify the functions of ATM and ATMIN in response to replication stress, we utilized both transcriptomics and quantitative mass-spectrometry-bas...

8,5'-cyclo-2'-deoxyadenosine (cdA) and 8,5'-cyclo-2'-deoxyguanosine generated in DNA by both endogenous oxidative stress and ionizing radiation are helix-distorting lesions and strong blocks for DNA replication and transcription. In duplex DNA, these lesions are repaired in the nucleotide excision repair (NER) pathway. However, lesions at DNA stran...

Tubulin is subjected to a number of posttranslational modifications to generate heterogeneous microtubules. The modifications include removal and ligation of the carboxy-terminal tyrosine of ⍺-tubulin. Whereas enzymes for most modifications have been assigned, the enzymes responsible for detyrosination, an activity observed forty years ago, have re...

Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, including Fanconi anemia (FA). We generated loss-of-function human haploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core complex, and used genome-wide CRISPR libraries as well as insertional...

Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, including Fanconi anemia (FA). We generated loss-of-function human haploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core complex, and used genome-wide CRISPR libraries as well as insertional...

Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the centra...

Hit list from the small molecule screen for all ten tumor suppressors.

Drug sensitivity data for lung cancer cell lines tested through the Cancer Cell Line Encyclopedia.

Supplementary Figures 1-13 and Supplementary Tables 1-5

Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ)...

We previously isolated from a Caenorhabditis elegans cDNA library, designed for two-hybrid screening, a gene encoding the DNA repair enzyme APN-1 using cross-specie complementation analysis of the Saccharomyces cerevisiae apn1∆ apn2∆ tpp1∆ triple mutant deficient in the ability to repair several types of DNA lesions including apurinic/apyrimidinic...

DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various pertubations, originating from endogenous or exogenous sources, can interfere with proper progression and completion of the replication process, thus threatening genome integrity. Coord...

The AP endonuclease activities towards 5OH-5Me-Hyd•A oligonucleotide duplex. The 3′-[32P]-labelled 5OH-5Me-Hyd•A oligonucleotide duplex was incubated with purified WT and mutant Nfo and APE1 under either standard condition “pH 7.6” for Nfo, or “NIR+Mg2+” same as “pH 6.9, 0.1 mM MgCl2” for APE1, or standard condition “BER+EDTA” same as “pH 7.6, 1 mM...

DNA repair activities towards 5-OH-Hyd residues in the extracts of Fanconi complementation group C cells. 5′-[32P]-labelled 5OH-Hyd•G oligonucleotide duplex was incubated with 20 µg of the extracts prepared from AHH1, FA-C and FA-C+FANCC cells. (A) Denaturing PAGE analysis of the reaction products. Lane 1, 5OH-Hyd•G treated with NEIL1; lane 2, 5OH-...

Comparison of the AP endonuclease activities towards urea, hydantoins and thymine glycol containing substrates. 5′-[32P]-labelled oligonucleotide duplexes were incubated with the purified WT and mutant Nfo and APE1 AP endonucleases under standard BER and NIR conditions. Nfo-G149G is a highly NIR-deficient mutant of Nfo; R177A and K98E are APE1 muta...

Comparison of the AP endonucleases and DNA glycosylases activities towards pyrimidine-derived hydantoins. Enzyme concentration dependence activity curves on 5′-[32P]-labelled oligonucleotide duplexes containing hydantoins (A) Nfo, Apn1 and APE1 acting on 5OH-Hyd•G; (B) Nfo, Apn1 and APE1 acting on 5OH-5Me-Hyd•A; (C) NTH1 and NEIL1 acting on 5OH-Hyd...

DNA repair activities towards 5OH-Hyd•G duplex in paraquat-induced E. coli cell-free extracts. 3′-[α-32P]-ddATP-labelled oligonucleotide duplexes were incubated with either 3 µg of cell-free extract or limited amount of a purified protein in the standard DNA glycosylase reaction “BER+EDTA” buffer for 30 min at 37°C. (A) Denaturing PAGE analysis of...

Oxidative damage to DNA, if not repaired, can be both miscoding and blocking. These genetic alterations can lead to mutations and/or cell death, which in turn cause cancer and aging. Oxidized DNA bases are substrates for two overlapping repair pathways: base excision (BER) and nucleotide incision repair (NIR). Hydantoin derivatives such as 5-hydrox...