Product Description
This digital document is a journal article from DNA Repair, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
One of the least well understood DNA repair processes in cells is the repair of DNA interstrand cross-links (ICLs) which present a major obstacle to DNA replication and must be repaired or bypassed to allow fork progression. Fanconi anemia (FA) is an inherited genome instability syndrome characterized by hypersensitivity to ICL damage. Central to the FA repair pathway is FANCD2 that is mono-ubiquitylated in response to replication stress and ICL damage through the action of the FA core complex and its E3-ubiquitin ligase subunit, FANCL. In its mono-ubiquitylated form FANCD2 is recruited to repair foci where it is believed to somehow coordinate ICL repair and restart of impeded replication forks. However, the precise mechanism through which the FA pathway and mono-ubiquitylation of FANCD2 promotes ICL repair remains unclear. Here we report on a functional homologue of FANCD2 in C. elegans (FCD-2). Although fcd-2 mutants are homozygous viable, they are exquisitely sensitive to ICL-inducing agents, but insensitive to ionizing radiation (IR). fcd-2 is dispensable for meiotic recombination and activation of the S-phase checkpoint, indicating that ICL sensitivity is likely due to a repair rather than a signalling defect. Indeed, we show that FCD-2 is mono-ubiquitylated in response to ICL damage and is recruited to nuclear repair foci. Consistent with the sensitivity of fcd-2 mutants, FCD-2 focus formation is induced in response to ICL damage and replication stress, but not following IR, suggesting that FCD-2 responds to lesions that block DNA replication and not DNA double strand breaks per se. The realization that the FA pathway is conserved in a genetically tractable model system will permit the comprehensive analysis of the interplay between the FA, homologous recombination (HR), translesion synthesis (TLS) and nucleotide excision repair (NER) pathways, critical to the understanding of ICL repair. ... Read more

Product Description
This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Fanconi anemia (FA) and cells lacking functional BRCA1 and BRCA2 proteins are hypersensitive to interstrand crosslinking (ICL) agents and show increased numbers of chromosomal breaks and radials. Although radial formation has been used to diagnose FA for more than 30 years, there has been little analysis of these characteristic formations. In this study, radials were analyzed from FA-A and FA-G fibroblasts as well as normal and retrovirally-corrected FA-A fibroblasts treated with high doses of ICLs. Radials were found to only involve non-homologous chromosome interactions and to be distributed nearly randomly along the length of chromosomes. Sites on chromosomes that did show increased frequency of radial involvement did not correlate with known fragile sites or pericentric regions. Hybrid radials were observed between mouse and human chromosomes in human-mouse hybrid cells produced by microcell-mediated chromosome transfer of mouse chromosomes into human FA-A fibroblasts. Both X and Y chromosomes were notably not involved in radials. These observations suggest that ICL repair may involve short stretches of homology, resulting in aberrant radial formation in the absence of FA proteins. ... Read more

Product Description
This digital document is a journal article from DNA Repair, published by Elsevier in . The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Unrepaired DNA double-strand breaks (DSBs) produced by ionizing radiation (IR) are a major determinant of cell killing. To determine the contribution of DNA repair pathways to the well-established cell cycle variation in IR sensitivity, we compared the radiosensitivity of wild-type CHO cells to mutant lines defective in nonhomologous end joining (NHEJ), homologous recombination repair (HRR), and the Fanconi anemia pathway. Cells were irradiated with IR doses that killed ~90% of each asynchronous population, separated into synchronous fractions by centrifugal elutriation, and assayed for survival (colony formation). Wild-type cells had lowest resistance in early G1 and highest resistance in S phase, followed by declining resistance as cells move into G2/M. In contrast, HR-defective cells (xrcc3 mutation) were most resistant in early G1 and became progressively less resistant in S and G2/M, indicating that the S-phase resistance in wild-type cells requires HRR. Cells defective in NHEJ (dna-pk"c"s mutation) were exquisitely sensitive in early G1, most resistant in S phase, and then somewhat less resistant in G2/M. Fancg mutant cells had almost normal IR sensitivity and normal cell cycle dependence, suggesting that Fancg contributes modestly to survival and in a manner that is independent of cell cycle position. ... Read more

Product Description
This digital document is a journal article from DNA Repair, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Fanconi anemia (FA) is a genetically heterogeneous disease characterized by developmental defects, progressive bone marrow failure and cancer susceptibility. Cells derived from patients with FA show spontaneous chromosomal aberrations and hypersensitivity to cross-linking agents, indicating a cellular defect in DNA repair. Among the 12 FA genes, only FANCD2, FANCL and FANCM have Drosophila homologs. Given this difference between the human and Drosophila FA pathways, it is unknown whether the fly homologs function in DNA repair. Here, we report that knockdown of Drosophila FANCD2 or FANCL leads to specific hypersensitivity to cross-linking agents. Further analysis revealed that FANCD2 and FANCL function in a linear pathway with FANCL being necessary for the monoubiquitination of FANCD2. FANCD2 mutants also exhibited the same defect in the ionizing radiation-inducible S-phase checkpoint that is seen in mammalian cells deficient for this gene. Finally, in an assay for inactivating mutations, FANCD2 mutants have an elevated mutation rate in response to nitrogen mustard, indicating that these flies are hypermutable. Taken together, these data demonstrate that Drosophila FANCD2 and FANCL play a critical role in DNA repair. Because of the lack of other FA genes, further studies will determine whether the conserved FA genes function as the minimal machinery or whether additional genes are involved in the Drosophila FA pathway. ... Read more

Product Description
This digital document is a journal article from Mut.Res.-Genetic Toxicology and Environmental Mutagenesis, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Particulate hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Cr(VI)-induced tumors exhibit chromosome instability (CIN), but the mechanisms underlying these effects are unknown. We investigated a possible role for the Fanconi anemia (FA) pathway in particulate Cr(VI)-induced chromosomal damage by focusing on the Fancg gene, which plays an important role in cellular resistance to DNA interstrand crosslinks. We used the isogenic Chinese hamster ovary (CHO) KO40 fancg mutant compared with parental and gene-complemented cells. We found that fancg cells treated with lead chromate had lower intracellular Cr ion levels than control cell lines. Accounting for differences of Cr ion levels between cell lines, we discovered that fancg cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, which was not observed after restoring the Fancg gene. Chromosomal damage was manifest as increased total chromosome damage and percent metaphases with damage, specifically an increase in chromatid and isochromatid breaks. We conclude that Fancg protects cells from particulate Cr(VI)-induced cytotoxicity and chromosome damage, which is consistent with the known sensitivity of fancg cells to crosslinking damage and the ability of Cr(VI) to produce crosslinks. ... Read more

Product Description
This digital document is a journal article from Mut.Res.-Genetic Toxicology and Environmental Mutagenesis, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.

Description:
Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital abnormalities, progressive bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA crosslinking agents. FA is a genetically heterogeneous disease with at least 11 complementation groups. The eight cloned FA proteins interact in a common pathway with established DNA-damage-response proteins, including BRCA1 and ATM. Six FA proteins (A, C, E, F, G, and L) regulate the monoubiquitination of FANCD2 after DNA damage by crosslinking agents, which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including DNA interstrand crosslinks. We have shown that FA-A fibroblasts are hypersensitive to both Cr(VI)-induced apoptosis and clonogenic lethality. Here we show that Cr(VI) treatment induced monoubiquitination of FANCD2 in normal human fibroblasts, providing the first molecular evidence of Cr(VI)-induced activation of the FA pathway. FA-A fibroblasts demonstrated no FANCD2 monoubiquitination, in keeping with the requirement of FA-A for this modification. We also found that Cr(VI) treatment induced significantly more S-phase-dependent DNA double strand breaks (DSBs), as measured by @c-H2AX expression, in FA-A fibroblasts compared to normal cells. However, and notably, DSBs were repaired equally in both normal and FA-A fibroblasts during recovery from Cr(VI) treatment. While previous research on FA has defined the genetic causes of this disease, it is critical in terms of individual risk assessment to address how cells from FA patients respond to genotoxic insult. ... Read more

Product Description
"A heartbreaking story, exquisitely told . . . Laurie Strongin's integrity, humanity, and wisdom are an inspiration to the rest of us."
--David Shenk, author of The Forgetting

Saving Henry is the eye-opening and inspiring story of how far a family will go to save the life of their child. Laurie Strongin's son Henry was born with a heart condition that was operable, but which proved to be a precursor for a rare, almost-always fatal illness: Fanconi anemia. Deciding to pursue every avenue that might provide a cure, Laurie and her husband signed on for a brand new procedure that combined in vitro fertilization with genetic testing to produce a baby without the disease, who could be a stem cell donor for Henry. As Laurie puts it: "I believe in love and science, nothing more and nothing less."

Laurie and her husband endured nine failed courses of the procedure before giving up. But Saving Henry is also about hope. It is the story of Henry, the feisty little boy who loved Batman, Cal Ripken Jr., and root beer-flavored anesthesia, and who captivated everyone with his spunk and positive attitude. When the nurses came to take blood samples, Henry brandished his toy sword and said, "Bring it on!" When he lost his hair after a chemo treatment, he declared, "Hey, I look like Michael Jordan!"

Laurie became a fervent advocate for stem cell research, working with policymakers and the scientific community to bring attention to Henry's case and to the groundbreaking research that could save many lives. Henry's courage and bravery inspired nurses, doctors, friends, and family. Saving Henry is the story of one family's search for a cure, and the long-lasting scientific impact their amazing little boy has had.

Praise for Saving Henry

"How do you make beauty and meaning out of unimaginable sorrow? Saving Henry is a stirring account of struggle, love, and loss that manages to be both honest and inspiring."
--Rabbi David Wolpe, author of Making Loss Matter and Why Faith Matters

"Henry's story is important and newsworthy; a testament to how the debate over medical technology and stem cell research is not just an academic argument, but also a searingly personal one. Mostly, though, it's an intimate love story. We should all learn from Henry what his family has learned--to live well and laugh hard."
--Lisa Belkin, journalist, The New York Times

"Saving Henry is a marvelously told tale of love triumphant. Parents often say they would do anything for their children. This is the story of a couple that actually did."
--Jeffrey Goldberg, national correspondent, The Atlantic

"There's a reason Saving Henry rings with so much truth: the author lived every word of it. It's a vivid, beautifully rendered, and almost painfully honest account of a journey none of them wanted to take, but could not avoid, thanks to a bad throw of the genetic dice. Laurie, her husband Allen, and especially little Henry, become pioneers in a landscape of complex technological procedures that offer hope but also bring pain . . . and yet they keep trying. This is a tale of a family that will not quit."
--John Donvan, correspondent, ABC News

"Strongin has a gift for telling a complex medical story as an unfolding family narrative--a family that in so many ways is my family, your family, anybody's family. Any of us in today's world could find ourselves facing the difficult and challenging set of decisions this family had to make. Strongin's story is a truthful and honest road map we may want to follow."
--Dr. Ranit Mishori, contributing health editor, Parade Magazine; professor, Georgetown University School of Medicine ... Read more

Customer Reviews (15)

Saving Henry: A Mother's Journey
An amazingly poignant story, well written and very personal. Brilliant to see such a moving story also be able to capture the realities of politics and science in a way that the reader can really understand. What a journy for this family and amazing contribution to other children that Henry made.

Inspiring read
An inspiring and heart-wrenching story beautifully told.If you ever need a reminder of what really matters in life... well, just follow Henry's lead.

Don't miss reading this book
I read this book because I heard about Henry from his aunt and I thought it would be a touching story.I truly did not expect to be captivated by the book from the very first pages.The writing is outstanding. I not only learned about how delightful of a child Henry was and the dedication of his parents and his community, this book is also a very personal look at the impact of politics on medical research. Please don't miss this book.

Incredible
This true story, will be the best read you have ever had about a family struggling to survive. I was captivated by it, and did not put it down until it was done.

Bravo to Laurie Strongin on the best writing ever done about Fanconi anemia.

Amazing book!
This book was great! My family recently went through the same situation with my niece but it was, in some ways, really amazing to read about it from different eyes. Laurie did a wonderful job of explaining the science of this disease so that people not close to the disease can really understand it better....I am excited and honored to meet her at an upcoming book party! I will be recommending this book to a lot of friends who know some of what my family went through and many people that don't! Thank you for sharing with us Laurie! ... Read more