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IMF-091-01-0001-en	How does origin licensing ensure that each genomic segment is normally copied only once per cell cycle?	Inactive helicases are loaded at origins in late mitosis and gap one, and in synthesis phase kinases activate a subset; activation prevents relicensing until the next cycle.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0002-en	Why does replication require primers, and what happens to them on the lagging strand?	Replicative polymerases cannot begin de novo, so primase in the polymerase-alpha complex makes short RNA-DNA primers; on the lagging strand these are removed, gaps filled, flaps processed and ligase seals the backbone.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0003-en	Why is one new strand synthesised continuously and the other as Okazaki fragments?	The strands are antiparallel and polymerases extend only from a free three-prime hydroxyl in the five-prime-to-three-prime direction, so only the leading strand can grow continuously toward the fork.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0004-en	How does PCNA make replicative synthesis processive?	The sliding clamp encircles DNA and tethers the polymerase to the template; clamp loaders use ATP to place it on DNA.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0005-en	Why must epigenetic information be actively re-established after the fork passes, unlike DNA sequence?	Modifications are not copied by base pairing; after histones are recycled and new ones deposited, reader-writer complexes and the local transcriptional environment help rebuild the marks.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0006-en	What do checkpoint kinases do at stalled forks, and why does failure of fork rescue matter for cancer?	They stabilise forks, restrain new origin firing, regulate repair and delay the cycle; unresolved replication stress creates chromosome breaks and rearrangements, a major source of cancer evolution.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0007-en	Why do telomeres shorten progressively in many somatic cells?	Conventional lagging-strand synthesis cannot fully copy the extreme chromosome end, and nucleolytic processing removes further sequence.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0008-en	What does shelterin prevent, and what follows when telomeres become critically dysfunctional?	Shelterin stops chromosome ends being mistaken for double-strand breaks; critically dysfunctional telomeres activate checkpoints, fuse, or generate breakage-fusion cycles.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0009-en	How does telomerase lengthen telomeres, and why can both too little and too much telomere maintenance be harmful?	It is a reverse transcriptase that extends repeats from its own RNA template; shortening limits replicative lifespan, while inappropriate maintenance permits malignant immortality.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0010-en	What distinguishes a DNA lesion from a mutation?	A lesion is chemical damage to DNA, whereas a mutation is a persistent sequence change that becomes fixed after replication or erroneous repair.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0011-en	How do polymerase proofreading and mismatch repair differ in timing and target?	Proofreading uses a three-prime-to-five-prime exonuclease to remove a misinserted nucleotide immediately; mismatch repair acts after replication on escaped mismatches and small insertion-deletion loops by excising a stretch of new strand.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0012-en	Why do inherited mismatch-repair defects in Lynch syndrome produce microsatellite instability?	Repetitive microsatellite sequences are especially prone to replication errors, so when mismatch repair fails these errors persist and the repeats become unstable.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0013-en	A tumour shows loss of a mismatch-repair protein on immunohistochemistry. Why does this not by itself establish Lynch syndrome?	Absent staining can result from an inherited variant, a somatic event, or epigenetic silencing, so the abnormal screen must be interpreted to distinguish them.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0014-en	How does base-excision repair remove a small non-distorting lesion such as uracil or an oxidised base?	A lesion-specific glycosylase removes the base, leaving an abasic site; an endonuclease cuts the backbone, the sugar phosphate is processed, and polymerase and ligase fill and seal.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0015-en	Why can PARP inhibition selectively kill homologous-recombination-deficient tumour cells?	Unrepaired single-strand lesions are converted into toxic replication-associated breaks that these cells cannot repair, a synthetic lethality; restored repair or fork protection can cause resistance.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0016-en	What triggers global-genome versus transcription-coupled nucleotide-excision repair?	Global-genome surveillance scans broadly for bulky helix-distorting lesions, whereas transcription-coupled repair is triggered when RNA polymerase stalls on a lesion in an active gene.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0017-en	Why do xeroderma pigmentosum and Cockayne-spectrum disease differ clinically although both involve nucleotide-excision repair?	Xeroderma pigmentosum defects cause extreme ultraviolet sensitivity and skin and eye cancers, whereas Cockayne defects impair transcription-coupled responses, causing growth and neurological disease; different regions and responses are compromised.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0018-en	Why is MGMT repair called a suicide reaction, and why does its tumour silencing matter for treatment?	MGMT transfers the alkyl group from guanine to itself and is then degraded, so each molecule acts once; tumours that silence it are more sensitive to some alkylating agents.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0019-en	Why is homologous recombination favoured in synthesis and gap-two phases, and how does it achieve accurate repair?	It needs a sister chromatid as template; ends are resected to single-stranded DNA, a RAD51 filament searches and invades the homologous sequence, and templated synthesis restores the sequence accurately.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0020-en	Why are germline BRCA status, tumour repair phenotype, and current drug sensitivity not interchangeable?	Tumours carry genomic scars recording past homologous-repair deficiency but may restore function through secondary mutations, so historical deficiency need not mean current sensitivity.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0021-en	What distinguishes classical non-homologous end joining from homologous recombination in timing, use and cost?	It ligates broken ends without a long homologous template, works throughout the cycle and is essential for antigen-receptor rearrangement, but can leave small insertions or deletions.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0022-en	Why does the Fanconi phenotype depend on more than the missing repair activity?	Interstrand-crosslink repair overlaps with other pathways, so disease also reflects tissue exposure to endogenous aldehydes and replication demand, as in marrow failure.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0023-en	What trade-off do translesion polymerases make?	Their specialised active sites copy across damaged templates and prevent prolonged fork collapse, but with lower fidelity, so switching back to the replicative polymerase is essential and excessive bypass increases mutation.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending
IMF-091-01-0024-en	How do ATM and ATR differ in the damage they sense, and what does p53 do with the signal?	ATM responds strongly to double-strand breaks and ATR to replication-associated single-stranded DNA; p53 integrates damage with arrest, senescence, repair or apoptosis.	Integrated Medical Foundations; chapter 91, TTS module 1; https://theisegoria.github.io/medical-textbook/integrated-medical-foundations-expanded-english.md; module SHA256 at export: 0baed2abd84317dae7541690fdac91b31f63fd32fde7c2be28b253813250f588; editorial review pending	imf lang::en chapter::091 module::091-01 review::pending