PhD student, Zewail City of Science and Technology
DNA is the hereditary material in living organisms that decides for their fate and therefore, it has to be accurately preserved. When cells encounter DNA damage, it should be rapidly repaired otherwise, the organism has to face a lot of negative consequences. DNA damage is linked to a various range of diseases including neurodegenerative diseases such as Alzheimer and Parkinson’s, mitochondrial dysfunction and premature aging. In addition, DNA damage is also linked to all cancer types including liver and breast cancers; the two most prevalent cancers among men and women in Egypt, respectively. The most common DNA damage type is ribonucleotides (rNTPs) misincorporation in the DNA consisting only of deoxyribonucleotides. This kind of damage is linked to gene mutations, chromosomal aberration, replication fork stalling, neurodegenerative diseases and hypothesized to be linked to cancer. The misincorporated rNTPs are mainly removed from the genome by enzymes known as Ribonucleases H1 and 2 (RNase H1 and RNase H2). Our research group is particularly interested in the mechanisms that prevent ribonucleotides incorporation in the genome and the mechanisms that repair this kind of damage when it takes place.
Abstract: The information encoded in DNA is influenced by the presence of non-canonical nucleotides, the most frequent of which are ribonucleotides. In this Review, we discuss recent discoveries about ribonucleotide incorporation into DNA during replication by the three major eukaryotic replicases, DNA polymerases α, δ and ε. The presence of ribonucleotides in DNA causes short deletion mutations and may result in the generation of single- and double-strand DNA breaks, leading to genome instability. We describe how these ribonucleotides are removed from DNA through ribonucleotide excision repair and by topoisomerase I. We discuss the biological consequences and the physiological roles of ribonucleotides in DNA, and consider how deficiencies in their removal from DNA may be important in the aetiology of disease.
Pub.: 21 Apr '16, Pinned: 30 Oct '17
Abstract: Despite more than 50 years of research, the vast majority of the biology of poly(ADP-ribosyl)ation (PARylation) still remains a gross mystery. Originally described to be a part of the DNA repair machinery, poly(ADP-ribose) (PAR) is synthesized immediately by poly(ADP-ribose) polymerases (PARPs, also known as ARTDs) upon DNA damage and then rapidly removed by degrading enzymes. PAR provides a delicate and spatiotemporal interaction scaffold for numerous target proteins. Thus, the multifaceted PARylation system, consisting of PAR itself and its synthesizers and erasers, plays diverse roles in the DNA damage response (DDR), in DNA repair, transcription, replication, chromatin remodeling, metabolism and cell death. In this review, we summarize the current understanding of the biology of PARylation, focusing on the functionality and the activities of the PARPs' founding member PARP1/ARTD1, which is modulated by a variety of posttranslational modifications. We also discuss the homeostasis of PAR - a process which is maintained by the balance of PAR synthesizers and erasers. We aim to sensitize the scientific community to the complexity of PAR homeostasis. Finally, we provide some perspective on how future research could try to disentangle the biology of PARylation - perhaps the most sophisticated, but still intricate posttranslational modification described to date.
Pub.: 25 Sep '16, Pinned: 30 Oct '17
Abstract: Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRK1A kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer’s disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity.
Pub.: 06 Jun '16, Pinned: 30 Oct '17
Abstract: The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase-induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers.
Pub.: 20 Feb '15, Pinned: 30 Oct '17