Neil Johnson, PhD

Neil Johnson, PhD
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This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
Learn more about Research Volunteering.

Professor
Nuclear Dynamics and Cancer Program
Co-Director, Biological Imaging Facility
 

Research Program

Educational Background

  • BSc, Genetics and Biochemistry, Newcastle University, Newcastle upon Tyne, UK, 2002
  • PhD, Cancer Biology and Therapeutics, Newcastle University, Newcastle upon Tyne, UK, 2006

Honors & Awards

  • AACR-Aflac Scholar-in-Training Award, 2011
  • Claudia-Adams Barr Program in Innovative Cancer Research Award, Dana-Farber Cancer Institute, 2012
  • Susan G. Komen Career Catalyst, 2013
  • FCCC-UPEN Ovarian SPORE Career Development Award, Fox Chase Cancer Center, 2013
  • Ovarian Cancer Academy Award, Department of Defense, 2014

People

Additional Staff

Former Lab Members

john-krais

 

John Krais, PhD, BS
Assistant Research Professor
Room: P2101 | 215-728-7077 | [email protected]

Alice Bradbury

 

Alice Bradbury, PhD
Postdoctoral Associate
Room: P2101 | 215-728-7133 | [email protected]

 

Emma Clausen, BA
Scientific Technician I
Room: P3101 | 215-278-7020 | [email protected]

 

Joseph Nacson, MD
Graduate Student
Room: P3101 | 215-728-3604 | [email protected]

 

 

Gregory Conway, PhD, MA
Postdoctoral Associate
Room: P2101 | 215-728-7133 | [email protected]

 

Pooja Patel
Scientific Technician
Room: P2101 | 215-728-7020 | [email protected]

Research Interests

BRCA biology and therapy resistance

  • Study and characterization of mRNA and protein products generated from germline BRCA mutant alleles.
  • The role of mutant BRCA proteins in the DNA damage response.
  • The role of BRCA proteins in DNA replication.
  • Mechanisms of resistance to PARP inhibitor and platinum therapy.

Lab Overview

The Johnson laboratory studies mechanisms of DNA damage detection, repair, and signaling that occur in BRCA1 mutation-containing organisms and cancers. We use a range of approaches, including cell biology, mouse genetics, and therapy resistance modeling, to understand basic biological processes and their implications for tumorigenesis and chemotherapy sensitivity. 

Figure 1. The homologous recombination (HR) spectrum over the life course of a BRCA1 mutant cancer. Arrows along the x axis indicate significant events over the course of cancer development and progression. Shading colors correspond to cancer development, cancer growth, PARPi and Platinum therapy (P+P) responsiveness and resistant growth.
Figure 1. The homologous recombination (HR) spectrum over the life course of a BRCA1 mutant cancer. Arrows along the x axis indicate significant events over the course of cancer development and progression. Shading colors correspond to cancer development, cancer growth, PARPi and Platinum therapy (P+P) responsiveness and resistant growth.

 

Lab Description

Dr. Neil Johnson is an associate professor with tenure at Fox Chase Cancer Center (FCCC) and leads an NCI R01-funded research program. Dr. Johnson’s laboratory studies mechanisms of DNA damage detection, repair, and signaling that occur in BRCA1 mutation-containing organisms and cancers. A range of approaches are routinely employed, including cell biology, mouse genetics, and therapy resistance modeling, to understand basic biological processes and their implications for tumorigenesis and chemotherapy sensitivity. In particular, Dr. Johnson’s research has focused on the utility of PARP inhibitor (PARPi) therapy for the past 10 years. Dr. Johnson used small molecule inhibitors to convert homologous recombination (HR) proficient cancer cells into HR-deficient cells, inducing ‘BRCAness’, and sensitizing cancers to PARPi. Subsequently, multiple contributions have been made toward understanding mechanisms by which BRCA1 mutation-containing alleles generate protein products that promote HR repair and chemotherapy resistance. More recently, several new BRCA1 mutant mouse alleles were generated in the Johnson laboratory to study the impact of loss of various BRCA1 functional domains on development and organismal health. Currently, the Johnson laboratory is continuing to explore DNA repair biology, and we aim to improve the current understanding of the role of BRCA1 in the repair of double stranded DNA breaks (DSBs) and maintaining genome stability. Central projects that are available to students are discussed below.

 

1. Determining the role of BRCA1 protein interactions in DNA repair, development and cancer.

The maintenance of genome integrity is essential for organismal development and preventing DNA damage-linked diseases such as cancer and Fanconi anemia (FA). Mutations in BRCA1 or PALB2 disrupt HR DNA repair and result in genome instability. The BRCA1 and PALB2 proteins directly heterodimerize through their respective coiled-coil (CC) domains, facilitating the formation of a larger BRCA1-PALB2-BRCA2-RAD51 complex that is required for RAD51 filament formation. BRCA1 and PALB2 form the only known interaction that is mediated by either proteins CC domain. Whether BRCA1 and PALB2 CC domains exclusively interact with one another, or there are additional CC interactions and functions is unknown. Because both BRCA1 and PALB2 form multiple protein complexes, specifically disrupting the CC domain is required to discern activities related to the BRCA1-PALB2 heterodimer. Our laboratory has developed novel BRCA1 and PALB2 CC domain mutant mouse models to investigate the significance of this interaction in DNA repair and organismal health. Brca1CCand Palb2CCalleles each have a 3-amino acid deletion in the CC domain that disrupt the BRCA1-PALB2 association but maintain protein stability and non-CC protein interactions.  Collectively, we are using biochemical, cell-based, and mouse genetic experiments to evaluate the nature and importance of the BRCA1-PALB2 interaction in DNA repair and maintaining genomic integrity.

2. Identifying new biological mechanisms of BRCA1-associated DNA repair.

An accumulation of DNA breaks or large insertions and deletions can induce loss of cellular and organismal viability, as evidenced by early embryonic lethality observed in Brca1 knockout mouse models. Paradoxically, BRCA1 mutant and wild-type cancers are equally viable and malignant. To sustain viability in the absence of BRCA1, cancers require adaptations that promote the repair of endogenous DNA damage. BRCA1 mutant cancers invariably harbor TP53 mutations, and loss p53 signaling can rescue the embryonic viability of mice harboring hypomorphic Brca1 alleles. However, the embryonic viability of Brca1 null alleles cannot be rescued with Tp53 knockout. Cells harboring more deleterious BRCA1 mutant alleles may require additional epi/genetic alterations to maintain viability. In this project, we are working on novel mechanisms of DNA repair pathway re-wiring that are responsible for sustaining the viability of BRCA1 mutant cancers; with the goal of providing new insights into cellular conditions that foster genome instability and carcinogenesis.

3. Uncovering therapy response determinants in BRCA1-mutation carrying tumors.

Patients with BRCA1 mutations have better therapy response and overall survival outcomes compared to BRCA1 wild-type patients. Mutations located in exon 11 of the BRCA1 gene represent approximately 30% of the overall number of BRCA1 mutation carriers that develop cancer in the US. We recently demonstrated that BRCA1 exon 11 mutation carriers had a significantly worse overall survival compared to patients with mutations outside of this exon, and outcomes were similar to the BRCA1 wild-type patient group.  Cancers with exon 11-located mutations are capable of expressing the BRCA1-Δ11q alternative splice (AS) isoform that lacks the majority of exon 11, including stop codon-inducing mutations. Currently, little is known about the ability of BRCA1-Δ11q to repair DNA damage, maintain genome integrity, and induce chemo-resistance. In this project, we are assessing the role of BRCA1-Δ11q, and the splice factors that regulate its production, in DNA repair, tumor development and therapy sensitivity. Many BRCA1 mutation-carrying patients develop therapy resistance; new biological insights gained here may result in opportunities for the design of improved prevention or treatment strategies that optimally target BRCA1 mutant cancers.

Selected Publications

Krais J.J., Wang Y., Patel P., Basu J., Bernhardy A.J.,Johnson N., Rnf168-mediated localization of bard1 recruits the brca1-palb2 complex to DNA damage. Nat Commun. 12(1): 5016, 2021. PMC8373961. https://www.ncbi.nlm.nih.gov/pubmed/34408138.

Johnson N, Speirs V, Curtin NJ and Hall AG. A comparative study of genome-wide SNP, CGH microarray and protein expression analysis to explore genotypic and phenotypic mechanisms of acquired antiestrogen resistance in breast cancer. Breast Cancer Res Treat 2008 Sep;111(1):55-63. PubMed

Johnson N, Cai D, Kennedy RD, Pathania S, Arora M, Li YC, D’Andrea AD, Parvin J.D and Shapiro GI. CDK1 participates in BRCA1-dependent S phase checkpont control in response to DNA damage.  Molecular Cell 2009 Aug 14;35(3):327-39. PubMed

Johnson N, Bentley J, Wang LZ, Newell DR, Robson CN, Shapiro GI, Curtin NJ. Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen sensitive and resistant breast cancer cells. Br J Cancer  2010 Jan 19;102(2):342-50. PubMed

Johnson N and Shapiro GI. Targeting cyclin-dependent kinases for cancer therapy. Cell cycle deregulation in cancer; GH Enders (ed.) 2010.

Johnson N, Shapiro GI. Cyclin-dependent kinases (CDKs) and the DNA damage response: rationale for CDK inhibitor-chemotherapy combinations as an anticancer strategy for solid tumors. Expert Opin Ther Targets. 2010 Nov; 14(11):1199-212. PubMed

Johnson N, Li Y-C, Walton ZE, Cheng KA, Li D, Rodig SJ, Moreau LA, Unitt C, Bronson RT, Thomas HD, Newell DR, D’Andrea AD, Curtin NJ, Wong KK, Shapiro GI.  Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.  Nature Medicine 2011 Jun 26;17(7):875-82. PubMed

Johnson N, Shapiro GI. Chemotherapy-induced p53-dependent and -independent DNA damage responses are enhanced by poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-proficient cancer cells. Cell Cycle. 2012 Feb 1;11(3). PubMed

Johnson N, Shapiro GI. Cyclin-dependent kinase 4/6 inhibition in cancer therapy. Cell Cycle. 2012 Nov 1;11(21):3913. PubMed

Johnson N, Johnson SF, Yao W, Bernhardy AJ, Wang Y, Li Y-L, Choi Y-E, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell M, Liu JF, D’Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6. PubMed... Expand

Additional Publications

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This Fox Chase professor participates in the Undergraduate Summer Research Fellowship
Learn more about Research Volunteering.