Dr John J Reynolds MBiolSci, PhD

Institute of Cancer and Genomic Sciences
Research Fellow

Contact details

Email: j.j.reynolds@bham.ac.uk

Address: Institute of Cancer and Genomic Sciences
IBR West Extension
College of Medical and Dental Sciences
University of Birmingham
Edgbaston
Birmingham B15 2TT

Dr John Reynolds is a Research Fellow in the laboratory of Professor Grant Stewart. His main area of expertise is in understanding the cellular response to DNA damage, and the link between defective DNA repair and human disease.

Dr John Reynolds has published papers in top journals such as Nature Genetics, Molecular Cell and Nucleic Acids Research and has given numerous talks and poster presentations at both national and international conferences.

Dr John Reynolds also teaches on several courses offered at the College of Medical and Dental Sciences.

Qualifications

PhD in Biochemistry (2011)
MBiolSci Undergraduate Masters in Genetics and Microbiology (2006)

Biography

Dr John Reynolds received his first degree in Genetics and Microbiology at the University of Sheffield (2006). He subsequently joined the laboratory of Professor Keith Caldecott to undertake his PhD studies. Here Dr Reynolds worked on characterising the molecular defects behind the rare human diseases AOA1 (ataxia oculomotor apraxia 1) and MCSZ (microcephaly, early-onset, intractable seizures and developmental delay), which are caused by mutations in the DNA single-strand break repair factors APTX and PNKP, respectively.

Following the completion of his PhD, Dr John Reynolds joined the laboratory of Professor Grant Stewart at the University of Birmingham as a Post-Doctoral Research Fellow. During his time at Birmingham, Dr John Reynolds has been working on the identification and characterisation of novel DNA damage response genes.

In 2015 Dr John Reynolds published a study in Molecular Cell, examining the role of a previously uncharacterised DNA damage response protein, BOD1L, in the suppression of deleterious resection of damaged replication forks.

Following this, in 2017 Dr John Reynolds published a paper in Nature Genetics, identifying mutations in DONSON as a common cause of microcephalic dwarfism, and establishing DONSON as a critical replication fork stability factor required for genome stability.

Dr John Reynolds aims to continue studying the mechanisms underlying DNA damage response and repair pathways, and investigating the roles they play in maintaining human health.

Teaching

MBChB Year 2 : Cancer: Causes to Cures Module
BMedSci Year 2: Advanced Molecular Experimental Genetics module
BMedSci Year 3: DNA damage pathways in human disease

Postgraduate supervision

Dr John Reynolds has supervised summer students, and MRes and PhD students on projects focused on studying the link between the DNA damage response and human disease.

Research

DNA Damage and Human Disease

The DNA in our cells is constantly being damaged from external and internal sources. To combat this, and to prevent genome instability, cells have evolved a multitude of efficient DNA repair pathways that detect, signal and repair DNA damage.

The importance of these DNA repair pathways is highlighted by the existence of numerous human genetic diseases associated with mutations in DNA repair factors. There are two major classes of symptoms associated with defective responses to DNA damage: increased pre-disposition to cancer and deficiency of the central nervous system.

The study of these human diseases has provided invaluable insight into the mechanisms of how cellular DNA repair pathways function to maintain genome stability and protect human health.

DNA Replication and DNA damage

Accurate and efficient duplication of the genome is essential for the continuation of life, and anything that obstructs or slows DNA replication is collectively called ‘replication stress’. An inability to deal with replication stress leads to genome instability and contributes to the development of human disease. In particular, replication stress is strongly linked to the development of cancer, and mutations in genes involved in responding to replication stress are typically associated with developmental defects. To genome instability, numerous factors function within the cellular response to replication stress to ensure DNA replication forks progress efficiently and are protected from damage.

DNA Single Strand Repair

DNA single strand breaks (SSBs) are some of the most commonly occurring types of DNA lesion that arise in the cell. If left unrepaired, a SSB can be converted into the more genotoxic DNA double strand break (DSB) by collision with an ongoing replication fork. SSBs are repaired by overlapping repair pathways collectively termed DNA single-strand break repair (SSBR). The human central nervous system seems to be particularly sensitive to SSBR defects, as mutations in SSBR proteins give rise to either neurodevelopmental defects (microcephaly) and/or neurodegeneration (cerebellar ataxia).

Other activities

Member of the Biochemical Society (Individual Early Career Researcher)
Member of the British Society for Cell Biology (BSCB)
Member of the British Association for Cancer Research (BACR)
Member of the European Association for Cancer Research (EACR)
Reviewer for grant funding bodies and journals.

Publications

Kalasova I, Hanzlikova H, Gupta N, Li Y, Altmuller J, Reynolds JJ, Stewart GS, Wollnik B, Yigit G, Caldecott KW. (2019) Novel polynucleotide 5’-kinase 3’-phosphatase mutations causing defective DNA strand break repair and protein poly (ADP-ribose) polymerase 1 hyperactivity in microcephaly with early onset seizures (MCSZ) Neurology Genetics

LC Burrage*, Reynolds JJ*, Baratang NV, Phillips JB, Wegner J, McFarquhar A, Higgs MR, Christiansen AE, Lanza D, Seavitt J, Jain M, Li X, Parry DA, Raman V, Chitayat D, Chinn IK, Bertuch AA, Karaviti L, Schlesinger AE, Earl D, Bamshad M, Savarirayan R, Doddapaneni H, Muzny D, Jhangiani SN, Eng C, Gibbs RA, Bi W, Emrick L, Rosenfeld JA, Postlethwait J, Westerfield M, Dickinson M, Beaudet A, Ranza E, Huber C, Cormier-Daire V, Shen W, Mao R, Heaney JD, Orange JS, University of Washington Center for Mendelian Genomics, Undiagnosed Diseases Network, Bertola D, Yamamoto GL, Baratela WAR, Butler MG, Ali A, Adeli M, Cohn DH, Krakow D, Jackson AP, Lees M, Offiah AC, Carlston CM, Carey JC, Stewart GS, Bacino CA, Campeau PM, Lee B. (2019) Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes American Journal of Human Genetics *Equal contribution

Agost LM, Luessing J, van Beneden A, Eykelenboom J, O’Reilly D, Bicknell LS, Reynolds JJ, van Koegelenberg M, Hurles ME, Brady AF, Jackson AJ, Stewart GS, Lowndes NF. (2018) Analysis of novel missense ATR mutations reveals further evidence for splicing defects underlying Seckel Syndrome Human Mutation

Grand RJA, Reynolds JJ. (2018) DNA Repair and Replication: Mechanisms and Clinical Significance Garland Science Book

Higgs MR, Sato K, Reynolds JJ, Begum S, Bayley R, Goula A, Vernet A, Paquin KL, Skalnik DG, Kobayashi W, Takata M, Howlett NG, Kurumizaka H, Kimura H, Stewart GS (2018) Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2 Molecular Cell

Read ML, Fong JC, Modasia B, Fletcher A, Imruetaicharoenchoke W, Thompson RJ, Nieto H, Reynolds JJ, Bacon A, Mallick U, Hackshaw A, Watkinson JC, Boelaert K, Turnell AS, Smith VE, McCabe CJ. (2017) Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer. Oncogene

Reynolds JJ*, Bicknell LS*, Carroll P*, Higgs MR*, Shaheen R*, Murray JE*, Papadopoulos DK, Leitch A, Murina O, Tarnauskaitė Ž, Wessel SR, Zlatanou A, Vernet A, von Kriegsheim A, Mottram RM, Logan CV, Bye H, Li Y, Brean A, Maddirevula S, Challis RC, Skouloudaki K, Almoisheer A, Alsaif HS, Amar A, Prescott NJ, Bober MB, Duker A, Faqeih E, Seidahmed MZ, Al Tala S, Alswaid A, Ahmed, Al-Aama JY, Altmüller J, Al Balwi M, Brady AF, Chessa L, Cox H, Fischetto R, Heller R, Henderson BD, Hobson E, Nürnberg P, Percin EF, Peron A, Spaccini L, Quigley AJ, Thakur S, Wise CA, Yoon G, Alnemer M, Tomancak P, Yigit G, Taylor AM, Reijns MA, Simpson MA, Cortez D, Alkuraya FS, Mathew CG, Jackson AP, Stewart GS. (2017) Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism Nature Genetics. *Equal contribution

Clarke TL, Sanchez-Bailon MP, Chiang K, Reynolds JJ, Herrero-Ruiz J, Bandeiras TM, Matias PM, Maslen SL, Skehel JM, Stewart GS and Davies CD. (2016) PRMT5-dependent methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombination Molecular Cell.

Paucar M, Malmgren H, Taylor M, Reynolds JJ, Svenningsson P, Press R, Nordgren A. (2016) Expanding the ataxia with oculomotor apraxia type 4 phenotype Neurology Genetics.

Higgs MR*, Reynolds JJ*, Winczura A, Blackford AN, Borel V, Miller ES, Zlatanou A, Nieminuszczy J, Ryan EL, Davies NJ, StankovicT , Boulton SJ, Niedzwiedz W, Stewart GS. (2015) BOD1L is required to suppress deleterious resection of stressed replication forks. Molecular Cell. *Equal contribution

Reynolds JJ, Stewart GS. (2013) A nervous predisposition to unrepaired DNA double strand breaks. DNA Repair Review

Reynolds JJ, Stewart GS. (2013) A single strand that links multiple neuropathologies in human disease BrainReview

Reynolds JJ, Walker AK, Gilmore EC, Walsh AC, Caldecott KW. (2012) Impact of PNKP mutations associated with microcephaly, seizures and development delay on enzyme activity and DNA strand break repair Nucleic Acids Research.

Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, Bodell A, Barry B, Gleason D, Allen K, Ganesh VS, Chang BS, Grix A, Hill RS, Topcu M, Caldecott KW, Barkovich AJ, Walsh CA. (2010) Mutations in PNKP cause microcephaly, seizures and defects in DNA repair Nature Genetics.

Reynolds JJ, El-Khamisy SF, Caldecott KW. (2009) Short-patch single-strand break repair in ataxia oculomotor apraxia-1 Biochemical Society Transactions. Review

Reynolds JJ*, El-Khamisy SF*, Katyal S, Clements P, McKinnon PJ, Caldecott KW. (2009) Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1 Molecular and Cellular Biology.*Equal contribution

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